TCM&GMJ, April 2018 E—ISSN 2346-8491
Inside this issue:
The Level of Endothelin-1 as a Risk Factor for Complications of Acute Epididymitis VOLUME 3, ISSUE 1
The Significant gap between new HIV infections and new diagnoses in the APRIL 2018 Eastern European country of Georgia
Assessment of cardiac autonomic neuropathy in young diabetics with postural orthostatic tachycardia syndrome (POTS)
Hernioplasty with new antiseptic poly- meric biocomposite meshes
Use of Chitosan/Poly ethylene gly- col scaffold and Wharton jelly- Publishers: derived mesenchymal stem cell in-
creases angiogenesis in the damaged Ivane Javakhishvili Tbilisi State University (TSU) Gender differences in coronary colat- teral circulation during acute and stable
ischemic heart disease Georgian Medical Association (GMA)
To fill the missing fragments of a complex mosaic of liver regenera- tion Tbilisi, Georgia www.tcm.tsu.ge
p 1 TCM&GMJ Vol. 3 Issue 1. 2018
Editorial Board
Co-chairmen: Prof. Gia Lobzhanidze MD, PhD (GMA, Tbilisi, Georgia) Prof. Archil Khomasuridze MD, PhD (TSU, Tbilisi, Georgia)
Board members: Mikheil Jangavadze MD, PhD Zaza Khachiperadze MD, Keti Tsomaia MD, Tinatin Asatiani LLM
Editorial Council
Chairman Prof. Aleksandre Tsiskaridze MD, PHD (TSU, Tbilisi, Georgia)
Members by Sections
Basic Medicine Clinical Medicine Zaal Kokaia MD, PhD (Lund University, Lund, Sweden) Aleksandre Aladashvili MD, PhD (TSU, Tbilisi, Georgia) Dimitri Kordzaia MD, PhD (TSU, Tbilisi, Georgia) Rezo Gagua MD, PhD (TSU, Tbilisi, Georgia) Teimuraz Jorbenadze MD, PhD (TSU, Tbilisi, Georgia) Giorgi Galdava MD, PhD (TSU, Tbilisi, Georgia) Liana Gogiashvili MD, PhD (Institute of Morphology, TSU, Georgia) Fridon Todua MD, PhD (TSU, Tbilisi, Georgia) Zurab Tsagareli MD, PhD (Institute of Morphology, TSU, Georgia) Tamar Kezereli MD, PhD (TSU, Tbilisi, Georgia) Nodar Chichinadze MD, PhD (TSU, Tbilisi, Georgia) Merab Kiladze MD, PhD (TSU, Tbilisi, Georgia) Diana Dzidziguri PhD (TSU, Tbilisi, Georgia) Vladimer Margvelashvili MD, PhD (TSU, Tbilisi, Georgia) Nana Doreuli PhD (TSU, Tbilisi, Georgia) Nino Okribelashvili MD, PhD (TSU, Tbilisi, Georgia) Gela Lezhava PhD (TSU, Tbilisi, Georgia) Mikheil Omiadze MD, PhD (TSU, Tbilisi, Georgia) Ramaz Gakhokidze PhD (TSU, Tbilisi, Georgia) Rusudan Karseladze MD, PhD (TSU, Tbilisi, Georgia) Nana Koshoridze PhD (TSU, Tbilisi, Georgia) Romani Shakarashvili MD, PhD (TSU, Tbilisi, Georgia) Ramaz Katsarava PhD (TSU, Tbilisi, Georgia) Teimuraz Chigogidze MD, PhD (TSU, Tbilisi, Georgia) Nodar Khodeli MD, PhD (Institute of Morphology, TSU, Georgia) Tengiz Tsertsvadze MD, PhD (TSU, Tbilisi, Georgia) Zurab Chkhaidze MD, PhD (Institute of Morphology, TSU, Georgia) Nino Gordadze MD, PhD (Institute of Morphology, TSU, Georgia) Bezhan Tsinamdzghvrishvili MD, PhD (TSU, Tbilisi, Georgia) Maia Mchedlishvili MD, PhD (Institute of Morphology, TSU, Georgia) Zurab Kakabadze MD, PhD (Tbilisi State Medical University, Tbilisi, Georgia) Tamar Ghvamichava MD, PhD (Institute of Morphology, TSU, Georgia) Alexandre Makatsariya MD, PhD (Moscow State Medical University, Alexander Truskinovsky MD (Roswell Park Cancer Institute, Buffalo, NY) Moscow, Russia) José M. Peinado Herreros MD, PhD (GSU, Granada, Spain) Pavel Poredos MD, PhD (Medical Faculty in Ljubljana, Slovenia) Vladimer Ovcharov MD, PhD (BMU, Sofia, Bulgaria) Vladimir Alexi-Meskhishvili MD, PhD (German Heart Institute, Berlin, Alexi Baidoshvili MD, PhD (Free University Medical Center, Amsterdam, Germany) The Netherlands) Edouard Matevossian MD, PhD (Munich Technical University, Munich, Chris Meijer MD, PhD (Free University Medical Center, Amsterdam, Germany) The Netherlands) Dietrich Doll MD, PhD (Hannover University, Hannover, Germany) Ekaterine Berishvili MD, PhD ( Albert Einstein College of Medicine NY, USA) Marom Sareli MD, PhD (Sackler School of Medicine, Tel Aviv, Israel) Nina Atanassova PhD, DSci ( Institute of Experimental Morphology, Pathology Thierry Berney MD (University of Geneva, Geneva, Switzerland ) and Anthropology with Museum )
Public Health and Preventive Medicine Palliative Medicine Paata Imadze PhD (TSU, Tbilisi, Georgia) Dimitri Kordzaia MD, PhD (TSU, Tbilisi, Georgia) Ketevan Dadiani PhD (TSU, Tbilisi, Georgia) Tamar Rukhadze MD, PhD (TSU, Tbilisi, Georgia) Lasha loria PhD (TSU, Tbilisi, Georgia) Elene Janberidze MD, PhD (Institute of Morphology, TSU, Tbilisi, Georgia) Nata Kazakhashvili PhD (TSU, Tbilisi, Georgia) Stein Kaasa MD, PhD (Norwegian University of Science and Technology, Nino Chikhladze PhD (TSU, Tbilisi, Georgia) Oslo, Shota Tsanava PhD (TSU, Tbilisi, Georgia) Julia Verne BSc, MBBS, MSc. PhD, FFPH (University of the West of Andrey Kehayov MD, PhD (Bulgarian Medical Union) England, Bristol, UK) Oleg Musiy MD, PhD (Kiev, Ukraine) MD, PhD (University of Brasov, Romania) Katalin Muszbek MD (Hungarian Hospice Foundation, Hungary) Frank D Ferris, MD (Palliative Medicine, Research & Education, Ohio Health Columbus, Ohio, USA)
p 2 TCM&GMJ, April 2018 Contents
Research Article
The Level of Endothelin-1 as a Risk Factor for Complications of Acute Epididymitis 4-7 Yevhen Lytvynets , Vasyl Balabanyk The Significant gap between new HIV infections and new diagnoses in the Eastern European 8-12 country of Georgia Nikoloz Chkhartishvili, Natia Dvali, Marine Karchava, Manana Ghvaberidze, Tamar Tchelidze, Tengiz Tsertsvadze Assessment of cardiac autonomic neuropathy in young diabetics with postural orthostatic 13-16 tachycardia syndrome (POTS) Musharaf Bashir, Sheikh Imran Sayeed, Suhail Ahmad
Hernioplasty with new antiseptic polymeric biocomposite meshes 17-19 Margalita Gogoladze, Merab Kiladze, Tamaz Chkhikvadze
Use of Chitosan/Poly ethylene glycol scaffold and Wharton jelly-derived mesenchymal stem 20-24 cell increases angiogenesis in the damaged sciatic nerve Mehrnaz Moattari, Gholamreza Kaka , Homa Mohseni Kouchesfahani, Majid Naghdi Seyed , Homayoon Sadraie
Literature Review
Gender differences in coronary colatteral circulation during acute and stable ischemic heart 25-31 disease Maia Chigogidze, Nino Sharashidze, Zurab Paghava To fill the missing fragments of a complex mosaic of liver regeneration 32-37 Keti Tsomaia, Nino Inauri, Leila Patarashvili, Nino Karumidze, Elza Azmaipharashvili, Irakli Bebiashvili, Mtvarisa Kordzaia, Manana Kakabadze, Diana Dzidziguri, Dimitri Kordzaia
p 3 TCM&GMJ, April 2018 Lytvynets et al
The level of endothelin-1 as a risk factor for complications of acute epididymitis
Lytvynets Y.1 Balabanyk V.2
Abstract
Background: Acute epididymitis is an inflammation of the epididymis. It mostly occurs unilaterally and may spread to the testis (‘epididymoorchitis’) if untreated. In this research there was made an attempt to clarify the diagnostic and prognostic significance of changes of the endothelin-1 (Et-1) content in blood plasma of the patients, suffering from acute epididymitis in connection with violation of blood circulation in testis with appendage. Materials and Method: To determine the concentration of Et-1, the method of immune-enzyme analysis was used. A signifi-
cant increase of the Et-1 concentration was revealed in all the examined patients before treatment. Results and Discussion: In the preoperative period, in 43% of patients with irreversible complications (lack of blood flow to a testicle or appendage, the Doppler-signal) the high concentration of Et-1 remained to the 7th day (25,8 ± 3,2 ng/ml, exceed- ing the norm by 2,5 times), which indicated the irreversible microcirculatory disorders in testicle (appendage), probably because of the increasing of vasoconstriction of blood vessels. In 57% of patients there was no development of complications, ischem- ic processes were reversible, and under this the concentration of Et-1 gradually decreased, and until the 14th day it was up to 5,8 ± 0,6 ng/ml, returning to the normal range. Conclusion: The dynamics of change of Et-1 concentration in blood plasma indicates the reversibility of metabolic disorders, related to ischemia of the testicle appendage tissue, as well as the diagnostic and prognostic significance of this factor determi- nation concerning the risk of complications development. TCM-GMJ April 2018; 3 (1):P4-P7)
Keywords: acute epididymitis, endothelial dysfunction, endothelin-1, Doppler, predicting complications.
Introduction of the inflammatory process of the testicle appendage. Endothelial dysfunction (ED) can be a self-causing cute epididymitis is an infectious and inflamma- disturbance of blood circulation in the organ, as it often tory disease of the testicle appendage that lasts provokes angiospasm or vascular thrombosis4,5. The en- less than 6 weeks. In some cases, the inflamma- dothelium function is regulated by nitrogen monoxide A 6,7,8 tory process spreads on a testicle along with the (NO) . appendage, and then an epididymo-orchitis is meant. One of the most important derivatives of the endo- Acute epididymitis represents a common medical condi- thelium is endothelin (Et). It is the most powerful vaso- tion in the urological outpatient clinic. Mostly, epididy- constrictor of the bloodstream, the synthesis of which is mitis is caused by bacterial ascent through the urogenital enhanced with various pathological processes. Nitric ox- tract, with pathogens originating either from sexually ide and other substances produced by the endothelium transmitted diseases or urinary tract infections. Although dilate blood vessels, which leads to stimulation of Et for- conservative antimicrobial therapy is possible in the ma- mation. In addition, beside the vasoconstrictor effect, Et jority of patients and is usually sufficient to eradicate the is involved in the regulation of cell growth. Nowadays it is pathogen, studies have shown persistent oligozoospermia known 3 types of Et: Et-1, Et-2, Et-3, which are the and azoospermia in up to 40% of these patients.1, 2 products of 3 different genes and have expressed differ- Heavy epididymo-orchitis can lead to ischemia of the ences in the structure and vasoconstrictor activity9,10,11. testicle tissue both due to the involvement of the organ After damage of the tissue, the endothelin system tissue in the inflammatory process, and through the com- reacts first, a sharp increase in the level of Et-1 in the pression of the blood vessels of the testicle by swollen plasma is a marker of the activity of the destruction pro- tissue of the appendage3. Vascular factor plays a signifi- cess. They are diagnostic markers of the involution pro- cant role in the development as well as in the termination cesses, reorganization and destruction of collagen and elastin of the connective tissue of the scar12. From the 1Urologycal Department, Ivano-Frankivsk National Medical University, Ivano-Frankivst, Kyiv, Ukraine; 2Urologycal Department The dynamics of changing concentration of Et-1 in National Military Medical Clinical Center, Kyiv, Ukraine the blood plasma indicates the reversibility of metabolic Received November 05, 2017; accepted March 24 , 2018. disorders, as well as the diagnostic and predictive signifi- Address requests to: Vasyl Balabanyk E-mail: [email protected] cance of the determination of this factor in relation to the Copyright © 2018 Translational and Clinical Medicine-Georgian risk of complications development5.
4 TCM&GMJ Vol. 3 Issue 1 2018 Lytvynets et al The study of biochemical markers of acute epididymo- the inflammation zone at the expense of microcirculation orchitis has a great theoretical and practical interest in terms improving in the pelvic organs. of dynamic observation of treatment and recovery of pa- For the patients of all 2 groups the therapy was com- tients. One of the possible markers may be endothelin-1 (Et bined with the physiotherapeutic procedure “Bioptron” on -1), which is a factor of endothelial dysfunction. the affected side of the wicket. The effectiveness of the carried therapy was analyzed in 7 and 14 days after the received therapy and evaluated the Materials and method safety of the use of drugs. The evaluation of the effective- The purpose of the study is to study the diagnostic and ness of therapy was assessed as excellent when the index prognostic significance of the endothelin-1 level in the plas- of IR (index of resistance) approached the norm (= 0.5), ma of patients’ blood regarding to the risk of complications good – the absence of clinical symptoms, the IR – less development in the treatment of acute epididymitis. than 0.5, satisfactory – the presence of clinical symptoms, The main criteria that allowed to participate in the bad – the lack of treatment effect. study were: the age from 26 to 72 years; the body weight The obtained results were analyzed using the computer was in average 78,3 ± 5,2 kg; body mass index – 25,6 ± 2,3 software packages of the STATISTICA licensed software kg/m2, of the patients which receive baseline therapy. The StatSoft Inc. and Excel XP for Windows using parametric patients with testicular twisting and obvious signs of puru- and non-parametric computing methods. lent epididymitis (epididymo-orchitis) were not included in the study. The examination and complex treatment of 35 patients Results and discussion with acute epididymo-orchitis have been performed. The control group consisted of 15 practically healthy men. Ul- The results of studying the dynamics of the level of Et- trasound signs and major Doppler parameters - peak systol- 1 in the blood plasma of patients in different periods of ic velocity/speed (PSS), peak diastolic velocity/speed (PDS) the survey are reflected in the chart. and index of resistance (IR) - were determined during the The patients in each group had got the developing study. complications during the treatment or treatment was inef- Endothelin-1 in blood plasma was determined using a fective, which determined the need for surgical treatment: set of firm "Biomedica" for quantitative determination of epididymotomy, epididymectomy, resection of the ap- endothelin-1 by immunoassay. The normal values of endo- pendage, orchithomy. Operative treatment was usually thelin-1 in human plasma of an anticoagulant EDTA are 0- done on the 5-7th day of hospitalization. 10 ng/ml. To determine the state of the endothelium of the In the preoperative period in the patients with acute vessels, the ratio of PSS of the patient to the healthy side complicated epididymo-orchitis, the concentration of Et-1 and the IR of the testicular artery from the patient side was exceeded the control (median of physiological values of used. the concentration of Et-1 in blood plasma) in average in Patients were divided into 2 groups. The first group - 2,5 times (p <0,05), which may be due to a destructive 20 patients with acute epididymoorchitis, in the process of process. treatment of which the antibiotic ofloxacin, l-arginine and In the preoperative period, there were statistically sig- suppositories with streptokinase 15 000 MU and nificant differences in the concentration of this marker in streptodornase 1250 MU were included, the 2nd group - 15 the studied groups, which was characterized by different patients with acute complicated epididymitis (epididymo- condition of the disease. In the 1st group of the patients orchitis), which were surgically treated. The control group is on the 5-7th day of hospitalization, the Et-1 content de- practically healthy men (15 men). creased slightly to 11,4 ± 2,1 ng/ml, and on the 14th day it In order to improve the efficiency of treatment and was 5,8 ± 0,6 ng / ml (p<0,05), which was put into the long-term therapeutic effect, l-arginine was included in range of norm (0-10 ng/ml). In the 2nd group of the pa- combination therapy of the patients of the 1st Group, tients with an adverse preoperative condition in the early which is a substrate for NO-synthase – an enzyme that treatment period on the 5-7 days, further increase in the catalyzes the synthesis of nitric oxide in the endothelial concentration of Et-1 (up to 25,8 ± 3,2 ng/ml) was noted, cells. The drug activates guanylatecyclase and increases the which, after the operative treatment, tended to decrease level of cyclic-guanidine-monophosphate (cGMP) in vas- and on the 14th day was 19,9 ± 2,2 ng / ml (p < 0,05), in cular endothelium, reduces the activation and adhesion of comparison with the 1st group in both periods of determi- leukocytes and platelets to the endothelium of blood ves- nation of Et-1 (Figure 1). sels, suppresses the synthesis of endothelin-1, which is a By analyzing the dynamics of an IR (according to the powerful vasoconstrictor and stimulator of proliferation Figure 2), a sharp decrease of the IR should have been not- and migration of smooth myocytes in the vascular wall. ed on the 5-7 day of the examination and treatment in the 2 Distreptaza was also used in the first group in the com- -nd group of patients, which indicated a deterioration in the plex treatment. The mechanism of the drug action lies in blood supply and haemodynamics of the affected append- the ability to lysis of necrotic masses, manure and fibrin age in the patients and required surgical treatment. As for deposits, which leads to resorption of connective tissue. the first group, the IR gradually increased, indicating im- Also the drug facilitates the access of antibacterial drugs to provement in blood supply and recovery of the patients. On the 14th day, an increase in the rate of IR in patients of
5 TCM&GMJ, April 2018 Lytvynets et al the 2nd group after the surgical treatment was noted: 0.48 cells of the smooth muscle of vessels, which results in a vs. 0,36, which was associated with the gradual recovery of vasospasm; in the case of low Et-1 concentration, the lig- the patients and the alignment of the hemodynamic index and-receptor complex Et-1 + Et-1B is formed and endo- to normal. thelium dependent vasodilatation develops. Therefore, it Thus, the statistical analysis data indicate that there are can be assumed that critical ischemia of the testicular tissue substantially significant differences both in absolute indexes is associated with vasoconstriction, which occurs when the and in dynamics of changes in the concentration of Et-1 in concentration of Et-1 increases, and it is such as to break the blood plasma of the patients of different groups during the processes that provide reparative regeneration. The the treatment, which is also confirmed by the dynamics of increase in the concentration of Et-1 (up to 25,8 ± 3,2 ng / IR. ml), detected by us, in 2.5 times in the early therapeutic It is known that the main stimulus of the formation period in the patients with acute purulent epididormorchitis and secretion of Et is ischemia or acute stress. Et, being a suggests that an increase in the level of Et-1 may have a powerful constrictor of the blood stream and an inflamma- prognostic and diagnostic value for definition of tactics tory peptide, causes an increase in the number of T- (conservative or operative) in the course of treatment. lymphocytes in the tissues and organs, which in its turn attracts other immunocompetent cells, in particular macro- Conclusion phages, which produce factors that stimulate inflammation and destruction of the hearth, which leads to unfavorable In all the examined patients with acute epididormorchi- prognosis for normal repair.11, 13 Some authors have tis accompanied by ischemia before surgery, a significant proven that macrophages can be differentiated into 2 sub- increase of the concentration of Et-1 in blood plasma was populations: the first ones are capable to destroy tumor detected. cells, and the latter – to increase their growth.14 The first In the preoperative period, in 43,0 % of the patients ones are characterized as cells with pronounced effector the irreversible complications developed that manifested properties that can participate in the protection against by necrosis of tissue of the testicle with appendage. At the both microorganisms and against malignant cells. They ac- same time, the concentration of Et-1 continued to increase tively produce various biologically active substances, in- until the 7th day (25,8 ± 3,2 ng / ml) and exceeded the cluding NO. Its excessive amount in combination with su- norm in 2,5 times, indicating irreversibility of microcircula- peroxide leads to the formation of peroxynitrite, which tion disorders in the body and requiring surgical treatment. violates the function of hemoglobin and causes hypoxia, In 57,0% of the patients treated with conservative which makes the processes of tissue regeneration worse15. treatment, complications were not noted, with the Et-1 Since Et has a predominantly local effect, it can be as- concentration up to the 14th day being 5,8 ± 0,6 ng / ml, sumed that the increase in its formation and its admission returning to the limit of the physiological norm. The dy- into the blood stream may be the cause of the appearance namics of the change in the concentration of Et-1 in the and deepening of the severity of the disease. It is known blood plasma of the patients of this group indicates the that at high Et-1 concentrations, it takes place its interac- reversibility of metabolic disorders associated with ische- tion with a specific receptor Et-1A, that is expressed on the mia of the tissues of the testicle.
Figure 1. Indexes of the content of Et-1 in the blood plasma of the patients with acute epididymoorchitis. 6 TCM&GMJ Vol. 3 Issue 1 2018 Lytvynets et al
Figure 2. Dynamics of the resistance index (IR) by groups.
References
1. Michel V, Pilatz A, Hedger MP, Meinhardt A. Epididymitis: revelations at the convergence of clinical and basic sciences. Asian Journal of Andrology. 2015; 17: 756-63. 2. Pilatz A, Hossain H, Kaiser R, et al.: Acute epididymitis revisited: impact of mo- lecular diagnostics on etiology and contemporary guide line recommendations. European Urology 2015; 68: 428-35. 3. Luzzi GA, O’Brien TS. Acute epididymitis. BJU Int. 2001; 87 (8): 747-55. 4. Vatutin NT, Kalinkina NV, Demidova AL. Endothelins and the results of multi- center research. Ukrainian journal of Cardiology. 2006; 1: 101-5. 5. Klimova YM, Kordon TI, Groma VG. The dynamics of endothelin-1 level and the development of postoperative complications in the patients, having been operated on colorectal cancer. Oncology. 2011; 13 (1): 247-50. 6. Abrahamovim OO, Faynik AF, Nechaj OV. The mechanisms of development of endothelial dysfunctions and its role in the pathogenesis of coronary heart disease. Ukrainian journal of Cardiology. 2007;. 1: 81-7. 7. Lytvynets YeA, Vintoniv OR, Kostenko LV. Color Doppler as method of detec- tion of vascular erectile dysfunction. Galician doctors magazine. 2013; 1: 34-6. 8. Draun M, Sommer F, Lehmacher W. Erectile dysfunction. Are interdisciplinary diagnosis and therapy necessary? Dtsch.Med.Wochenschr. 2004; 38 (3): 227-31. 9. Gozmakov OA. The system of endothelin peptide: the mechanisms of endovascular pathology. Cardiology. 2000; 1 (32): 9. 10. Klimova OM, Kryvorotko IV, Kordon TI. The diagnostic significance of indexes of immunoreactivity for prognosis impossibility of anastomoses in patients suf- fering from colorectal cancer. Kharkiv surgical school. 2011; 1 (46): 15-20. 11. Filayeva JA, Tenchurina TG. The homeostatic peculiarities of angiogenic factors during wound healing with hypertrophic scar after mammoplastic. The modern problems of science. 2007; 2: 73-7. 12. Pivovar SN. The dynamics of endothelin-1 level and functional state parameters of heart in patients with complicated course of myocardial infarction. Ukrainian medical journal. 2000; 4: 140-3. 13. Carncek P, Stewart DJ. Immunoreactive endothelin in human plasma: marced elevation in patients in cardivasculary shok . Biochem Biophys Res Commun. 1989; 161: 562-7. 14. Berezhna NM. The role of immunity system cells in the microenvironment of the tumor. Oncology. 2009; 11(39): 6-17. 15. Eltze E, Wild PJ, Wülfing C [et al.] Expression of the endothelin axis in noninva- sive and superficially invasive bladder cancer: relation to clinicopathologic and molecular prognostic parameters. Eur. Urol. 2009; 56 (5): 837-45.
7 TCM&GMJ, April 2018 Chkhartishvili et al .
The significant gap between new HIV infections and new diagnoses in the Eastern European country of Georgia Chkhartishvili N.1 Dvali N.1 Karchava M.1 Ghvaberidze M.1 Tchelidze T.1 Tsertsvadze T.1,2
Abstract
Background: HIV epidemic continues to grow in the Eastern European country of Georgia. It is well documented that peo- ple unaware of their HIV status are major contributors to the spread of the virus. Aim: The aim of this study was to estimate the number of new infections in 2015-2016 and to define the gap between the new infections and the diagnoses. Methods: The number of new HIV infections was estimated with two methods: recent infection testing algorithm (RITA) and Spectrum software modeling. RITA was conducted using limited antigen avidity (LAg) enzyme immunoassay (EIA) and inci- dence was estimated using McWalter/Welte formula. LAg EIA was performed according to the manufacturer’s instructions on frozen remnant specimens initially used for HIV diagnosis. HIV infection was defined as recent if an individual did not have any evidence of a longstanding infection and had a recent infection on LAg EIA. The study covered a two-year period of 2015 -2016. Results: Of 1421 (711 in 2015 and 710 in 2016) adults newly diagnosed with HIV, 1132 (80%) had complete data and quality blood specimens available and were included in RITA estimation. Among 1132 infections included 136 (12%) were classified as recent (13% in 2015 and 11% in 2016, p=0.33). Estimated 1300 persons were newly infected in 2015 and 1100 – in 2016
based on RITA-derived approach. Spectrum modeling showed that estimated 1100 persons were newly infected annually in 2015 and 2016. If all 1421 persons diagnosed during the study period were newly infected, then detection rate would be 59- 65%. However, after adjusting for 55% of late diagnoses reported during 2015-2016, detection rate dropped to 26-29%. Conclusion: Study demonstrates that there is a significant gap in diagnosis regardless of estimation method used. The sub- stantial number of HIV positive persons unaware of their status is likely to contribute to the growing HIV epidemic in the country. Increased efforts are needed to reduce the number of people living with undiagnosed HIV.TCM-GMJ April 2018; 3 (1):P8-P12)
Keywords: HIV, recent infection, incidence, Eastern Europe, Georgia
Introduction based on newly reported cases only. Information on true HIV incidence is crucial for the IV/AIDS is one of the major global health accurate assessment of HIV dynamics and consequently challenges, with estimated 36.7 million people for designing response interventions. At the same time, living with the disease1. A recent achievement direct measurement of the population incidence is virtual- H in HIV prevention and treatment reduced the ly impossible as it requires periodic HIV testing of an en- number of new infections globally. The progress has tire population, which is technically difficult and requires been documented in all regions of the world except East- substantial financial resources. To avoid these challenges ern Europe and Central Asia, where the number of new methods for indirect measurement of incidence are devel- infection increased by 60% between 2010 and 20161. oped, which includes assay-based recent infection testing The first case of HIV infection in Georgia was report- algorithm (RITA) and modeling-based approaches4,5. RI- ed in 1989. The number of new diagnoses had been in- TA relies on the ability of laboratory assay to distinguish creasing annually, reaching record 719 new diagnoss in between recent and old infections. 2016. However, a number of new diagnosis does not pro- The aim of the presented study was to estimate the vide an accurate picture of transmission dynamics be- incidence of HIV infection using RITA algorithm and cause many of the newly diagnosed people are actually mathematical modeling. infected for many years already. For example, more than half of newly reported cases in Georgia over the recent Methods years had been diagnosed late with CD4 cell count <350 cell/mm3 2, 3. This complicates incidence interpretation Assay-based incidence estimation This was a retrospective estimation of HIV incidence From the 1 Infectious Diseases, AIDS and Clinical Immunology Research within the case-based surveillance system. Study was con- Center, 16 Al. Kazbegi Avenue, Tbilisi 0160, Georgia ducted at the Infectious Diseases, AIDS and Clinical Im- 2IvaneJavakhishvili Tbilisi State University, Faculty of Medicine, 2 Chiau- reli St., Tbilisi 0159 Georgia munology Research Center (IDACIRC), which is Geor- Received March 07, 2018; accepted April 5 , 2018. gia’s referral institution for HIV diagnosis, treatment and Address requests to: Nikoloz Chkhartishvili, MD,MS,PhD E-mail: care. IDACIRC performs confirmatory testing of all ini- [email protected] tially reactive samples to confirm an HIV diagnosis. Rem- Copyright © 2018 Translational and Clinical Medicine-Georgian 8 TCM&GMJ Vol. 3 Issue 1 2018 Chkhartishvili et al . nant diagnostic specimens stored at the laboratory of HIV reporting to global AIDS monitoring, which has been vali- diagnostics of IDACIRC were used for assay-based inci- dated and approved by UNAIDS. dence estimation. RITA algorithm, applied within the study, relied on Ethics combining data for the laboratory assay for recent infec- tion and clinical/laboratory data as recommended by The study used only unique HIV system identifiers World Health Organization (WHO) and United Nations without any personal identifying information. The study Joint Program on AIDS (UNAIDS)4. For laboratory assay, was approved by the Institutional Review Board of the we used limiting antigen (LAg) avidity enzyme immune Infectious Diseases, AIDS and Clinical Immunology Re- assay (EIA) - Sedia™ HIV-1 LAg-Avidity EIA. search Center (OHRP #IRB00006106). Remnant diagnostic specimens from persons newly diagnosed in 2015 and 2016 were used for analysis. The Results and discussion study included only adult individuals aged at least 18 years old. Test for recent infection was performed and interpret- A total of 1421 adult persons were diagnosed in Geor- ed in accordance with the manufacturer’s instructions. At gia in 2015 and 2016 (711 in 2015; 710 in 2016). Out of the first stage of testing, long-standing infections were them 289 (20.3%) were excluded from RITA estimation identified, defined as specimens with normalized optical because of either volume/quality of remnant specimen or density (ODn) greater than 2.0. All specimens with ODn lack of 6-months clinical/laboratory data, necessary for ≤2.0 were re-tested using the same assay and specimens determining recent infection cases. Excluded persons did with ODn ≤1.5 were defined as recent infections. not differ on basic demographic and epidemiological char- Clinical and laboratory data were extracted from the acteristics from those retained in the analysis. national AIDS health information system and included Of 1132 persons included in the study 547 were diag- information about the presence of AIDS defining illness nosed in 2015 and 585 in 2016. The median age was 38 6 according to CDC classification , CD4 cell count, and years old, with persons aged 18 to 25 years old accounting HIV viral load. for 9% of the study population (table 1). Majority were HIV infection was defined as recent if the individual men - 853 (75.4%). The most frequent transmission mode had a recent infection on the LAg-Avidity assay and did was heterosexual contact - 599 (52.9%, including 266 not have clinical or laboratory of longstanding infection among women and 333 among men). Distribution by re- (Figure 1). gion of residence did not show statistical significance by Presence of recent infection was assessed among newly- year. Overall 393 (34.7%) persons were diagnosed in the diagnosed persons only using remnant diagnostic speci- capital city of Tbilisi alone, 501 (44.3%) in - Western mens. Evidence of longstanding infection was assessed Georgia and 238 (21.0%) in – Eastern parts of the country based on clinical and laboratory data obtained within 6 (Table 1). months of HIV diagnosis and included the history of pre- A total of 136 (12.0%) persons were determined to vious positive HIV test and diagnosis of AIDS, defined as have a recent infection on RITA. The proportion of per- 3 CD4 count <200 cells/mm or presence of AIDS-defining sons with recent infection did not differ by year (13.0% in 6 illness , within 6 months of HIV diagnosis. Given that 2015 vs. 11.1% in 2016, (p=0.33). probability of progression to AIDS stage without an- RITA-based estimation showed that the number of tiretroviral therapy is about 2% within the 2 years of infec- new infections was 1300 in 2015 and 1100 in 2016 (a total tion and 50% within the first 10 years of infection, diagno- of 2 400 new infections). Spectrum derived estimates were sis of AIDS within 6 months of HIV diagnosis is indica- 1100 new infections both in 2015 and 2016 (a total of 7,8 tive of late diagnosis rather than rapid progression . That 2200 new infections) (Figure 2). is why 6 month period after diagnosis was chosen for de- If all 1421 persons diagnosed in 2015-2016 were newly termining presence of AIDS. We also applied additional infected then detection rates for RITA estimation would criteria of HIV viral load of <1000 copies/ml within 1 be 59.2% (1421/2400), while for Spectrum estimation – month after HIV diagnosis indicating long-standing infec- 64.6% (1421/2200). However, given that 55.5% and tion. Studies have shown that addition of this criterion 55.1% of newly diagnosed persons in 2015 and 2016 pre- 9 improves the accuracy of identifying recent infection . sented to care late (CD4 count<350 cells/mm3), then of RITA based incidence was estimated using McWalter/ 1421 diagnosed persons only 635 had high CD4 cell count 10 Welte formula . Factors associated with recent HIV infec- and potentially could have been recently infected. Conse- tions were evaluated in modified multivariate Poisson re- quently, detection rate would be 26.5% (635/2400) for 11 gression analysis . SAS software was used for statistical RITA and 28.9% (635/2200) for Spectrum modeling. analyses. Factors associated with recent HIV infection were evaluated in multivariate analysis (Table 2). Results of re- Modeling-based incidence estimation gression analysis showed that younger age and sex be- tween men are main predictors of recent infection. Proba- For modeling-based estimation, we used Spectrum bility of having recent infection was significantly higher in projection software,5 widely used and recommended by men who have sex with men compared to any other trans- UNAIDS. The software methodology is updated annually mission category: relative risk (RR) 2.99 (95% CI: 1.72- and we have used the model created in 2017 for country
9 TCM&GMJ, April 2018 Chkhartishvili et al . 5.21, p=0.0001) compared to injection drugs users; RR tained low HIV prevalence among pregnant women 2.17 (95% CI: 1.41-3.33, p=0.0004) compared to hetero- (<0.04% over 2005-20016, data from the National Center sexually infected men and RR 1.61 (95% CI: 1.03-2.51, for Disease Control and Prevention), suggest that there is p=0.04) compared to heterosexually infected women. Be- no emergence of the independent epidemic among wom- cause of a small number of persons in transmission cate- en. gory of “other” (total 17 cases), this was excluded from As it would be expected younger age was significantly multivariate analysis. It should be noted that none of these associated with recent infection. However, we should un- 17 persons had a recent infection by RITA. It is important derscore that older people get infected as well with 5% of that heterosexually infected women had a relatively higher people aged 45 or more had evidence of recent infection. frequency of recent infection as compared to drug users This should be taken into account while designing re- and heterosexually infected men (Table 2). sponse intervention especially considering global data Methods used in the presented study obtained similar showing increase in a number of new infections among results. According to Spectrum estimation, the incidence older people18,19. of HIV infection in Georgia remained stable in 2015-2016, Presented study has both strengths and limitations. while RITA based methodology suggests a decrease in the The major strength of the study is the well-established number of new infections. Overall, both methods indicate AIDS service and surveillance system with the availability that unlike rest of the Eastern European region, the HIV of biological specimens and comprehensive electronic data incidence in Georgia is not increasing. on every diagnosed case of HIV infection. Use of clinical At the same time, both methods show that significant- and laboratory data for RITA based estimation reduced ly more people get infected than being diagnosed. Findings the probability of false-positive results and thus the validi- of this study suggest that in the best case scenario only ty of methodology used. 65.6% of those infected in 2015-2016 was diagnosed and On the other hand, surveillance system may also be this drops to 26.5% detection rate in the worst case sce- the reason for the limitation. The spectrum of newly diag- nario. Low detection rate is the major reason behind the nosed persons depends on testing practices and as men- gap in HIV diagnosis in the country with only 42% of tioned above there is low HIV testing coverage of key 12000 estimated number of people living with HIV are populations at risk, consequently, HIV positive persons aware of their disease. This has serious implications for who did not have access to testing services were not diag- HIV transmission trajectories, as it is well documented nosed and did not get into our study. This may have a bi- that people unaware of their positive HIV status continue ased result. Also there some limitation related to Spectrum to engage in high-risk behaviors unknowingly transmitting projection model, which largely relies on data from bio- the virus. People living with undiagnosed HIV represent behavioral surveys on HIV prevalence and population size the main source of epidemic growth12. estimates. Therefore, modeling depends on the representa- Low HIV detection rate results from low HIV testing tives of these surveys. coverage of key populations at risk, such as people who It should be noted that despite the major differences inject drugs (PWID) and men who have sex with men in methodology of two estimation approaches used in our (MSM). According to latest bio-behavioral surveys, only study, results were similar suggesting that these findings 25.7% of PWID and 44.3% of MSM received an HIV test, are valid reflecting existing tendencies in the country. which is obviously is not enough to fill up the existing gap13. Undoubtedly, without expanding testing coverage Conclusions improvement in detection rate would be impossible, espe- cially given that the HIV epidemic in Georgia remains The study allows making important conclusions. It concentrated among the key population. appears that incidence of HIV during the studied period at Our study showed that MSM have highest levels of least was stabilized, but because of the gap in detection recent infection, which was statistically significant in multi- rate, the epidemic continues to grow. MSM are at higher variate analysis and this has been shown in our previous risk for infection and it is possible that this population work14. This finding confirms surveillance and research becomes a major driver of the epidemic in the country. data indicating active ongoing transmission in MSM popu- Improving HIV diagnosis is crucial for ending the lation. Bio-behavioral surveys conducted over the last dec- AIDS epidemic through 90-90-90 strategy, which aims at ade show a dramatic increase in HIV prevalence from 4% diagnosing 90% of people living with HIV, to treat 90% of in 2005 to over 20% by 201513. More recent Georgian those diagnosed and to achieve viral suppression in 90% MSM cohort study showed high HIV incidence rate of 5.8 of those on treatment.20Georgia ensured universal access new infections per 100 person-years of follow-up15. to antiretroviral therapy since 2004 and this has translated The relatively higher rate of recent infection among into a dramatic decrease in HIV related mortality21,22. heterosexually infected women as compared to heterosex- Since 2015 Georgia implemented treat all policy and if the ually infected men and PWID deserves attention. It has country is able to reach the first 90 target of diagnosis, been shown that primary source of infection among wom- then ending the AIDS epidemic will become the realistic en is the HIV positive spouse/regular partner, which has and achievable goal. been confirmed both by surveillance and phylogenetic da- ta16,17.Analysis of case investigation data or recent period Acknowledgements shows that transmission trajectory remains the same from The study was supported by the Global Fund to Fight male regular partner to women. This, coupled with sus- 10 TCM&GMJ Vol. 3 Issue 1 2018 Chkhartishvili et al .
AIDS, Tuberculosis and Malaria (grant # GEO-H- NCDC/SR-1.5)
Table 1. Study population characteristics
Characteristic Distribution Total 2015 2016 (n=1 132) (n=547) (n=585) p value Age category, n (%) <25 102 (9.0) 60 (11.0) 42 (7.2) 0.09 25-<35 339 (30.0) 164 (30.0) 175 (29.9) 35-<45 358 (31.6) 175 (32.0) 183 (31.3) 45+ 333 (29.4) 148 (27.0) 185 (31.6) Gender, n (%) Men 853 (75.4) 135 (24.7) 144 (24.6) 0.98 Women 279 (24.6) 412 (75.3) 441 (75.4) Mode of HIV transmission, n (%) Heterosexual contact (women) 266 (23.5) 130 (23.8) 136 (23.3) 0.06 Heterosexual contact (men) 333 (29.4) 147 (26.9) 186 (31.8) Sex between men 192 (17.0) 110 (20.1) 82 (14.0) Injection drug use 324 (28.6) 153 (28.0) 171 (29.2) Other 17 (1.5) 7 (1.3) 10 (1.7) Region of residence, n (%) Western Georgia 501 (44.3) 258 (47.2) 243 (41.5) 0.15 Eastern Georgia 238 (21.0) 107 (19.6) 131 (22.4) Tbilisi 393 (34.7) 182 (33.3) 211 (36.1)
Table 2. Factors associated with recent HIV infection RR = Relative risk; 95% CI = 95% Confidence Interval
New infections, Multivariate analysis Total N n (%) p value RR 95% CI p value Age category <25 102 26 (25.5) <0.0001 2.99 1.56-5.75 0.001 25-<35 339 61 (18.0) 2.65 1.53-4.58 0.0005 35-<45 358 32 (8.9) 1.68 0.96-2.96 0.07 45+ 333 17 (5.1) 1 Gender Men 853 104 (12.2) 0.75 Women 279 32 (11.5) Mode of HIV transmission Heterosexual contact (women) 266 32 (12.0) <0.0001 1.86 1.09-3.18 0.02 Heterosexual contact (men) 333 32 (9.6) 1.38 0.80-2.40 0.25 Sex between men 192 53 (27.6) 2.99 1.72-5.21 0.0001 Injection drug use 324 19 (5.9) 1 Region of residence Western Georgia 501 51 (10.2) 0.18 0.93 0.65-1.33 0.69 Eastern Georgia 238 29 (12.2) 0.95 0.63-1.44 0.82 Tbilisi 393 56 (14.2) 1 Year of diagnosis 2015 547 71 (13.0) 0.33 1.03 0.75-1.40 0.87 2016 585 65 (11.1) 1
11 TCM&GMJ, April 2018 Chkhartishvili et al .
Figure 2. Estimated number of new infection and number of diagnosed infections, 2015-2016
Figure 1. Recent infection testing algorithm
References
1. UNAIDS. Ending AIDS: Progress towards the 90-90-90 targets. Global AIDS 16. Chkhartishvili N, McNutt L-A, Smith PF, Tsertsvadze T. Characteristics of HIV- Update. Geneva: UNAIDS; 2017. infected women and factors associated with HCV seropositivity in the Republic 2. Chkhartishvili N, Sharvadze L, Gabunia P, Abutidze A, Nikolaishvili M, of Georgia. AIDS Research and Therapy. 2011;8:25. Tsertsvadze T. Late HIV diagnosis in Georgia: public health and economic 17. Dvali N, Karchava M, Chkhartishvili N et al. Transmission clusters among newly implications. Translational and Clinical Medicine-Georgian Medical Journal. 2016;1:11- diagnosed HIV patients in the country of Georgia. Abstract # WEPEC639. 8th 14. IAS Conference on HIV Pathogenesis, Treatment and Prevention. Vancouver, BC, Cana- 3. Chkhartishvili N, Chokoshvili O, Bolokadze N et al. Late presentation of HIV da; 2015. infection in the country of Georgia: 2012-2015. PLoS One. 2017;12:e0186835. 18.Centers for Disease Control and Prevention. HIV Surveillance Report, 2016; vol. 4. Global HIV STrtaegic Information Working Group. Recent infection testing 28. . Atlanta: CDC; 2017. algorithm technical update: Applications for HIV surveillance and programme 19. Negin J, Gregson S, Eaton JW et al. Rising Levels of HIV Infection in Older monitoring. Geneva: UNAIDS; 2018. Adults in Eastern Zimbabwe. PLoS One. 2016;11:e0162967. 5. Stover J, Brown T, Puckett R, Peerapatanapokin W. Updates to the Spectrum/ 20. UNAIDS. 90–90–90 - An ambitious treatment target to help end the AIDS epidemic. Estimations and Projections Package model for estimating trends and current Geneva; 2014. values for key HIV indicators. AIDS. 2017;31 Suppl 1:S5-S11. 21. Tsertsvadze T, Chkhartishvili N, Sharvadze L et al. Outcomes of Universal 6. Centers for Disease Control and Prevention. 1993 revised classification system Access to Antiretroviral Therapy (ART) in Georgia. AIDS Res Treat. for HIV infection and expanded surveillance case definition for AIDS among 2011;2011:621078. adolescents and adults. MMWR Recomm Rep. 1992;41:1-19. 22. Chkhartishvili N, Sharvadze L, Chokoshvili O et al. Mortality and causes of 7. Brookmeyer R. Reconstruction and future trends of the AIDS epidemic in the death among HIV-infected individuals in the country of Georgia: 1989-2012. United States. Science. 1991;253:37-42. AIDS Res Hum Retroviruses. 2014;30:560-6. 8. Centers for Disease Control and Prevention. Vital signs: HIV testing and diagno- sis among adults-United States, 2001-2009. MMWR Morb Mortal Wkly Rep. 2010;59:1550-5. 9. Moyo S, Kotokwe KP, Mohammed T et al. Short Communication: Low False Recent Rate of Limiting Antigen-Avidity Assay Combined with HIV-1 RNA Data in Botswana. AIDS Res Hum Retroviruses. 2017;33:17-18. 10. McWalter TA, Welte A. Relating recent infection prevalence to incidence with a sub-population of assay non-progressors. J Math Biol. 2010;60:687-710. 11. Spiegelman D, Hertzmark E. Easy SAS calculations for risk or prevalence ratios and differences. Am J Epidemiol. 2005;162:199-200. 12. Skarbinski J, Rosenberg E, Paz-Bailey G et al. Human Immunodeficiency Virus Transmission at Each Step of the Care Continuum in the United States. JAMA Internal Medicine. 2015;175:588. 13. Country Coordinating Mechanism. Country Reports for Global AIDS Monitor- ing. Tbilisi: Country Coordinating Mechanism; 2005-2016. 14. Tsertsvadze T, Chkhartishvili N, Dvali N et al. Estimating HIV incidence in the eastern European country of Georgia: 2010-2012. Int J STD AIDS. 2014;25:913- 20. 15. Chokoshvili O, Kepuladze K, Tsintsadze M et al. High prevalence and incidence of HIV, syphilis and viral hepatitis among men who have sex with men in Geor- gia: Findings of the Georgian MSM Cohort. 16th European AIDS Conference. Mi- lan, Italy; 2017. 12 TCM&GMJ, April 2018 Bashir et al
Assessment of cardiac autonomic neuropathy in young diabetics with postural orthostatic tachycardia syndrome
Bashir M.1 Sayeed Sh. 1 Ahmad S. 1
Abstract
Background: One of the serious complications of diabetes mellitus is cardiac autonomic neuropathy (CAN) which may lead to life-threatening complications such as silent myocardial infarction. Autonomic neuropathy is one of the established causes of postural orthostatic tachycardia syndrome (POTS).
Aim: In this study, we performed various autonomic function tests in young diabetics who were diagnosed with POTS. Our aim was to assess the severity of CAN in them. Methods: 20 young diabetics mean age 16.5 years (SD 2.66) diagnosed with POTS were assessed for this study. Autonomic function tests such as deep breathing test (DBT), Valsalva ratio (VR), 30:15 ratio, lying to standing test (LST) and cold pressor test (CPT) were performed in all the subjects. Degree of CAN was assessed in them and categorized as per the severity. Result: In these subjects, we found that the symptoms of orthostatic intolerance such as a headache, sweating, palpitations etc were present in all the subjects. Autonomic function tests that were deranged are DBT (5%), VR (1%), 30:15 ratios (1%), LST (50%) and CPT (15%). In these subjects 10% subjects had “Early CAN”, 30% had “Definite CAN” and 60% had “Severe CAN”. Conclusion: Clinical assessment revealed that all the subjects had orthostatic intolerance and some degree of CAN. Further studies need to be carried out to assess the autonomic functions and severity of CAN in young diabetics with POTS for proper management which may help in improving quality of life in them. TCM-GMJ April 2018; 3 (1):P13-P16 )
Keywords: POTS, cardiac autonomic neuropathy, type1 diabetes mellitus, adolescents.
Introduction mon to find some degree of CAN in patients diagnosed with POTS preferentially impairment of sympathetic innervation of ostural orthostatic tachycardia syndrome (POTS) is the lower limbs7. Nearly half of the patients with POTS exhibit a form of dysautonomia associated with symptoms some signs of autonomic neuropathy8. of orthostatic intolerance such as nausea, blurring P of vision, light headedness and near syncope upon acquiring upright position1. These symptoms are immediately relieved by a recumbent posture1. The main char- Materials and methods acteristic feature of POTS in adults is a resting heart rate of ≥ 120 beats per minute (bpm) or an increase in the heart rate of ≥ 30 bpm upon standing within 10 minutes of head-up tilt test Study design and population or lying to standing test2. In young people such as adolescents, After obtaining clearance from the institutional ethical POTS is defined as a resting heart rate of ≥ 130 bpm or an committee we recruited 20 adolescents with type 1 diabetes increase in heart rate of ≥ 40 bpm upon acquiring an upright mellitus (T1DM) who were diagnosed with POTS from the posture within 10 minutes of standing3. Adolescence is a period outpatient department of Endocrinology, GMC Srinagar and of rapid growth and development which may lead to temporary SMHS hospital, J&K, India for this descriptive study. Prior to impairment in the flexibility of autonomic nervous system thus the commencement of study all the subjects or their caretakers leading to a physiological phenomena called as “developmental were consulted. They have explained the significance of this POTS” which usually peaks at around 14 years of age and fades study. Once they agreed to participate in this study informed away at around 19 years of age4. However, in young people, written consent was taken from the subjects or their caretakers. POTS may also occur as a result of autonomic neuropathy due Later they were invited to the autonomic function testing labor- to diabetes mellitus3. It must be noted that not all the patients atory in the Department of Physiology for assessment of CAN. with POTS exhibit peripheral or autonomic neuropathy5. Thus Subjects on drugs that tend to alter heart rate such as β adre- normally cardiac autonomic neuropathy (CAN) can’t be pro- nomimetics / blockers were excluded from this study posed as a mechanism underlying POTS6. Yet it is not uncom- Data collection Symptoms related to autonomic nervous system func- From the 1Department of Physiology, Government Medical College, Sri- tioning were assessed in all the subjects. All the subjects com- nagar, J&K, India. pleted a self-reported questionnaire to assess the severity of Received March 03, 2018; accepted March 24 , 2018. orthostatic intolerance. The questionnaire contained various Address requests to: Musharaf Bashir E-mail: [email protected] symptoms of orthostatic intolerance such as a headache, sweat- Copyright © 2018 Translational and Clinical Medicine-Georgian ing, palpitations etc. Later subjects were made to rest for at least
13 TCM&GMJ Vol. 3 Issue 1 2018 Bashir et al 15 minutes in a recumbent position before the beginning of sciousness upon acquiring upright posture. All these symptoms autonomic function tests for the assessment of CAN. Resting faded away upon acquiring a recumbent posture. Kanjwal K et blood pressure and heart rate were measured. Various autonom- al11 reported findings similar to our study. They recruited 300 ic function tests such deep breathing test (DBT); E/I ratio, subjects diagnosed with POTS and found that 18 of them devel- Valsalva ratio (VR), 30:15 ratio, cold pressor test (CPT) and oped syncope upon head-up tilt test (HUTT). lying to standing test (LST) were performed. The severity of CAN was assessed and divided on the basis of Ewing’s classifi- Autonomic function tests and CAN cation of autonomic failure9. All the subjects were made to rest in a recumbent position Analysis of data before beginning the procedure. Standard autonomic function tests like DBT, VR and 30:15 ratio (to assess parasympathetic activity) were performed in all subjects12. LST and CPT (to as- The data obtained have been presented in terms of percent- sess sympathetic activity) were also done (13). A rest of 5 minutes ages wherever applicable. was given in between all the tests. We observed that all patients had impaired parasympathetic and sympathetic activity which Result suggests the presence of CAN in them. Autonomic neuropathy in patients with POTS was also reported by Jacob G et al7 who The inclusion of patients and their characteristics compared the autonomic function tests of 10 patients diagnosed with POTS with age and sex-matched healthy controls. They Overall 20 adolescents with T1 DM who were diagnosed found that the autonomic function tests of POTS group were with POTS were selected for this study. Mean age of the pa- significantly reduced (p< 0.05) as compared to the controls. tients was 16.5 ± 2.66 years. All the patients were assessed for They concluded that patients with POTS had developed CAN. the symptoms of orthostatic intolerance and CAN. In another study Oner T et al14 studied 125 patients with symp-
toms of POTS. They found that patients with POTS had de- Findings ranged sympathetic functions and they concluded that these patients had autonomic neuropathy. In contrast to our findings, As shown in Table 1 most of the patients complained of Qi Fu et al15 in their study of 19 patients with POTS did not find weakness (85%), palpitations (80%) and headache (70%). Least autonomic neuropathy in them when compared to controls. common symptom reported by the subjects was hyperventila- Findings in our preliminary study suggest autonomic neuropathy tion (5%). Table 2 shows the various autonomic function tests in young diabetics with POTS. We observed that LST and CPT that were performed. We observed that LST was abnormal in 10 which are used to assess the sympathetic activity were abnormal patients (50%). DBT was abnormal in 5 patients (25%), CPT in 50% and 3% patients respectively. This means that sympa- was abnormal in 3 patients (15%) and both VR and 30:15 ratio thetic activity was impaired in most of the patients with POTS. were abnormal in 1 patient each (5%) as shown in Table 2. Other tests to assess parasympathetic activity such as DBT, VR Ewing’s criteria were used to assess the severity of CAN as and 30:15 ratio were deranged in 25%, 5%, and 5% patients shown in Table 3. As shown in Table 3 we observed that none respectively which means that parasympathetic activity was also of the patients had normal findings (0%), 2 patients (10%) had impaired in these patients. It may be concluded that CAN was “Early CAN”, 6 patients (30%) had “Definite CAN” and 12 present in young diabetics with POTS and most of them had patients (60%) had “Severe CAN”. abnormal sympathetic activity.
Assessment of severity of CAN in young diabet- Discussion ics with POTS
In adolescents, POTS is defined as an increase in heart rate CAN in these patients was assessed and graded according of ≥40 bpm upon acquiring upright posture within 10 minutes to Ewing’s classification of autonomic failure9. or a sustained resting heart rate of ≥ 130 bpm3. Diabetes melli- Normal: normal tests or one parasympathetic test borderline. tus is regarded as one of the important causes of POTS3. As Early CAN: 1abnormal parasympathetic test or 2 tests border- already mentioned nearly half of the patients with POTS exhibit line. CAN at some stage8. Definite CAN: ≥ 2 abnormal parasympathetic tests. Severe CAN: ≥2 abnormal parasympathetic tests + 1 abnormal Symptoms of orthostatic intolerance sympathetic test/ 2 borderline sympathetic tests. In our study, we found that CAN was present in all the subjects 20/20 (100%). Most of the patients had “Severe CAN” In our study, we observed that all the subjects had which means that both parasympathetic and sympathetic activity symptoms of orthostatic intolerance. The most common symp- was impaired in them with a sympathetic preponderance. As tom of orthostatic intolerance was a weakness (85%) which was already mentioned autonomic failure with a sympathetic prepon- described as tiredness by the subjects not related to the amount derance in patients diagnosed with POTS was also reported by of work done followed by palpitations (80%). Both these symp- Raj SR6 and Jacob G et al7 in their studies. We also observed, toms were reported upon standing up from a recumbent posi- “Early CAN” and “Definite CAN” in 10% and 30% of patients tion. Similar findings were reported by Kanjwal et al (10) who respectively which means that there is an excessive abnormality studied 9 patients diagnosed with POTS. They found that all the of parasympathetic activity in them. Thus we found CAN in all patients 9/9 (100%) developed fatigue and palpitations upon the young diabetics with POTS. acquiring upright posture. Presyncope/Syncope was found in 6 This study has limitations. We obtained the information patients (30%) of patients which were defined as lightheaded- regarding symptoms of POTS from all the subjects but we did ness, chest tightness, blurring of vision or transient loss of con-
14 TCM&GMJ, April 2018 Bashir et al
not perform HUTT in them to confirm POTS as the patients autonomic dysfunction which was graded accordingly. Our were already diagnosed. We did not perform heart rate variability thinking is that the loss of flexibility of autonomic nervous sys- analysis of these patients which would otherwise have been ben- tem has led to POTS in them. Appropriate treatment and coun- eficial. In our case sample size was small as it is very difficult to seling may be beneficial for them as it can improve their quality find young diabetics with POTS. One of the major limitations is of life. that we could not ascertain whether POTS in these patients re- sulted due a rapid spurt of growth in adolescence which is purely a physiological process or it was a result of diabetes mellitus that Acknowledgments these young patients were suffering from. Further studies with a large sample size are needed to confirm our findings and bio- We are extremely grateful to Dr.Riyaz Ahmad Lone for his chemical parameters such as fasting glucose and glycaemic con- contribution. trol (HbA1c) must be recorded to ensure a proper analysis. There is no conflict of interest. In conclusion, all the young diabetic patients diagnosed with No funding or financial support was received. POTS had symptoms of orthostatic intolerance that affected the quality of their life. Furthermore, all the patients had underlying
Table 1. Symptoms of orthostatic intolerance in young diabetics with POTS. Symptoms of Orthostatic intolerance (OI) Percentage of subjects with symptoms of OI Headache 70% Fatigue 50% Sweating 55% Palpitations 80% Weakness 85% Sleep disorder 25% Anxiety 20% Tremors 10% Hyperventilation 5% Dizziness/Vertigo 35% Presyncope/ Syncope 30%
Table 2. Autonomic function tests in young diabetics with POTS. Autonomic function tests Percentage (%) of subjects with abnormal tests. DBT 5 (25%) VR 1 (5%) 30:15 ratio 1 (5%) LST 10 (50%) CPT 3 (15%)
DBT -deep breathing test; VR -Valsalva ratio; 30: 15 ratio - ratio of maximum R-R interval at around 30th beat to the minimum R-R interval at around 15th beat; LST - lying to standing test; CPT-cold pressor test
Table3. Assessment of CAN in young diabetics with POTS as per Ewing’s classification of autonomic failure. Severity of CAN Young diabetics with POTS (n=20) Normal 0 (0%) Early CAN 2 (10%) Definite CAN 6 (30%) Severe CAN 12 (60%)
15 TCM&GMJ Vol. 3 Issue 1 2018 Bashir et al
Referencs
1. Low PA, Sandorini P, Joyner M, Shen W. Postural tachycardia syndrome (POTS). Journal of Cardiovascular Electrophysiology. 2009; 20(3): 352-58. 2. Schondorf R, Low PA. Idiopathic postural orthostatic tachycardia syndrome: an attenuated form of acute pandysautonomia? Neurology.1993; 43:132–37. 3. Grubb BP. The postural tachycardia syndrome: When to consider it in adoles- cents. Family Practice. 2006; 28(3): 19-30. 4. Grubb BP, Rowe P, Calkins H. Postural tachycardia, orthostatic intolerance, and the chronic fatigue syndrome. In: Grubb BP, Olshansky B, editors. Syncope: Mechanisms and Management. 2nd edition. Malden, Mass: Blackwell Publishing; 2005. p. 225-44. 5. Gibbons CH, Bonyhay I, Benson A, Wang N, Freeman R. Structural and Func- tional Small Fiber Abnormalities in the Neuropathic Postural Tachycardia Syn- drome. Plos One.2013; 8(12): 1-8. 6. Raj SR. Postural orthostatic tachycardia syndrome (POTS). Circulation. 2013; 127 (23); 2336-42. 7. Jacob G, Costa F, Shannon JR, Robertson RM .The neuropathic postural tachy- cardia syndrome. N Engl J Med. 2000; 343:1008–14. 8. Mizumaki K. Postural Orthostatic Tachycardia Syndrome (POTS). J Arrhythmia. 2011; 27(4): 289-306. 9. Ewing DJ, Martyn CA, Young RJ, Clarke BF. The value of cardiovascular auto- nomic function tests: 10 years of experience in diabetes. Diabetes Care. 1985; 8(5): 491-98. 10. Kanjwal K, Karabin B, Kanjwal Y, Grubb BP. Autonomic Dysfunction Present- ing as Postural Orthostatic Tachycardia Syndrome in Patients with Multiple Scle- rosis. Int J Med Sci. 2010; 7(2): 62-7. 11. Kanjwal K, Sheikh M, Karabin B, Kanjwal Y, Grubb BP. Neurocardiogenic syncope coexisting with postural orthostatic tachycardia syndrome in patients suffering from orthostatic intolerance: a combined form of autonomic dysfunc- tion. Pacing Clin Electrophysiol. 2011; 34(5): 549-54. 12. Ewing DJ, Clarke BF. Diagnosis and management of diabetic autonomic neurop- athy. British Medical Journal.1982; 285: 916-18. 13. Zygmunt A, Stanczyk J. Methods of evaluation of autonomic nervous system function. Arch Med Sci. 2010; 6(1); 11-18. 14. Oner T, Guven B, Tavli V, Mese T, Yilmazer MM. Postural Orthostatic Tachycardia Syndrome (POTS) and Vitamin B12 Deficiency in Adolescents. Pediatrics. 2014; 133(1): 138- 42. 15. Fu Q, VanGundy TB, Galbreath MM, Shibata S. Cardiac Origins of the Postural Orthostatic Tachycardia Syndrome. J Am Coll Cardiol. 2010: 55(25): 2858-68.
16 TCM&GMJ, April 2018 Gogoladze et al
Hernioplasty with new antiseptic polymeric biocomposite meshes
Kiladze M.1 Gogoladze M.2 Chkhikvadze T.3
Abstract
Introduction: Improving the results of hernia treatment and prevention of complications became a goal of our research which in•cluded two parts – experimental and clinical. Histomor•phological and bacteriological researches showed that the best result out of the 3 control groups was received in case of covering implant “Coladerm”+ with chlorhexidine.
Based on the experiment results working process continued in clinics in order to test and introduce new “coladerm”+ chlor- hexidine covered polypropylene meshes into practice. Materials and Methods: For clinical illustration, there were 110 pa•tients introduced to the researchers who had hernioplasty procedures by different nets: I group – standard meshes+”coladerm”+chlorhexidine, 45 patients; II group - standard meshes +”coladerm”, 35 patients; III group – standard meshes, 30 patients. Assessment of the wound and echo-control was done post -surgery on the 8th, 30th 60th and 180th days. Results: This clinical research based on the experimental results once again showed the best anti-microbe features of new anti- septic polymeric biocomposite meshes (standard meshes+”coladerm”+chlorhexidine); a timely termination of regeneration and reparation processes without any post-surgery suppurative complications. Conclusion: We hope that new antiseptic polymeric biocomposite meshes present•ed by us will be successfully used in the surgical practice of hernia treatment based on and supported by experimental-clinical research. (TCM-GMJ April 2018; 3 (1):P17-P19)
Keywords: hernia, antiseptic mesh, “coladerm”+ chlorhexidine covered poliprophilene meshes
Introduction ma, infiltration, chronic postoperative pain, discomfort, net migration and shortening of the net. Despite the not- ernia is one of the widespread surgical patholo- ed advances, there are common remaining unresolved gies as it is found in 4% of the population. complications regarding the safe and reliable closure of H Consequently annually up to 20-21 mln, hernio- the abdominal wall and infections associated with the use plasties are carried out worldwide1,4 .Despite of mesh. many years of experience in the field of hernia surgical We are presenting locally produced new antiseptic, treatment there still exist many unsolved problems such biodegradable, biocompatible polymer mesh that is cov- as the safe closure of defects of the abdominal cavity ered in Georgia Produced biodegradable, biomass poly- wall. Up to 200 methods of hernioplastics,2 various im- mer - „coladerm“ and +chlorhexidin to be used in mod- plantations and application of synthetic materials refer to ern prosthetic herniology. lack of the optimal surgical strategy. In modern herniolo- gy priorities are given to tension-free plastics. The merge of the synthetic implants and “tension free hernioplas- Material and methods tics” concepts enabled sharp reduction of the side effects list, making it possible to perform successful surgeries in The study consisted of two parts: Clinical and experi- that contingent whose treatment by the method of tissue- mental. The experimental study (period 15.11.2014- plasty was related with high risk of lethality3,4. Large-scale 15.04.2015y) included 21 rabbits, whose abdominal wall introduction of tension-free hernioplastics caused intensi- was implanted with polypropylene single standard light- fication of the associated problems such as migration, weight mesh with two types of coverage in three varia- dissection re-lapse, postoperative complications, hemato- tion. 1. Standard mesh; 2. Standard mesh + coladerm“; 3. Standard mesh + „coladerm“ + chlorhexidine. Each rab- bit had 6 mesh inserted each 10-20mm, totaling 126 units. From the I. Javakhishvili Tbilisi State Universiti, Medical Department, Faculty of Medicine; 2 New Vision University Hospital , 3 A. ladashvili During the experiment, meshes were removed from the Clinic, LTD; rabbits and their subsequent morphological and bacterio- Received July 12, 2017; accepted March 11 , 2018. logical studies were carried out in specialized laboratories Address requests to:Margalita Gogoladze E-mail:[email protected] in the timetable of the 14th, 30th, 45th, 90th and 180th days. Copyright © 2018 Translational and Clinical Medicine-Georgian Medical Journal
17 TCM&GMJ Vol. 3 Issue 1 2018 Gogoladze et al .
On the basis of the positive results from experimental (standard mesh+ „coladerm“ + chlorhexidine) to be used studies, we moved to the clinical part (period 10.02.2016 - in hernioplasty in modern practice successfully7. 20.02 .2017y)-that included - 110 patient with Diagnosis: Inguinal hernia73 patients and Ventral hernia - 37pa- tients.Implants were used in three variants: 1. Standard Conclusion mesh (30 patients); 2. Standard mesh + „coladerm“ (35 patients); 3. Standard mesh + „coladerm“ + chlorhexidine This new type polymer mesh successfully completed (45 patients). Before the surgery patients were filling out morphological, bacteriological and clinical studies, and consentson participation in the research5. today is widely used in surgical practice. 1. New antiseptic, polymeric, biocomposite mesh (standard mesh + „coladerm“ + chlorhexidine) is an opti- Result and discussion mal prosthetic material in modern herniology. 2. New mesh has the best antimicrobial properties. In the Results of the experiment: This new type polymer shortest possible time of implantation, the infection is in- mash successfully completed morphological and bacterio- hibited. Postoperative period is carried out without the logical study. "microbial contamination" and complications associated Morphological studies have show: By using of „new with Implantation. mesh“ there were regenerative processes complete on the 3. New antibacterial, polymeric, biocomposite mesh 90th day in the implantation zone without detection of (standard mesh + „colorerm“ + chlorhexidine) in the pe- inflammatory infiltrative vascular changes in the implanta- ripheral zone is characterized by the complete and effec- tion zone, with the formation of a solid dependent tissue tive course of reparative-regenerative reactions. With the of the tissue carcass, with the full placement of the mesh proven ultrasound control and clinical assessment. in the prosthetic area. The dissemination of the IV regen- 4. The regenerative-reparative processes between. new erative degree process and complete firmness was fixed5 antibacterial, polymeric, biocomposite mesh (standard (Figure: 1)(Figure: 2) mesh + „kolorerm“ + chlorhexidine) and the aponeurotic Bacteriological studies have shown: Following the ends in reasonable terms. IV regenerative degree of The use of the new mesh bacterial contamination was mini- distribution process and complete in growth is marked. mized (1,26%). Only in 1 out of the 126 implanted pros- 5. In case of using a new mesh, the projection area is free thetic materials was found the Candida albicans strain. from inflammatory infiltrative changes that provide the Bacterial contamination was reduced four times with the complete and guaranteed fixation of the mesh on the front use of new mesh. This will prevent the postoperative com- wall of the abdomen without complications associated plications and the likelihood of recurrence of hernia Scien- with the mesh. tific-practical value6. 6. In the postoperative period, none of the hyperthermia For the first time in Georgia, in 5 different Clinics at cases were observed in the use of new types of prosthetic the same time, operation -hernioplasty was performed material. User assessment and ultrasonographic surveyed with new, antiseptic, biocomposite mesh- Standart poly- operated area as clean. Hematoma, seroma, and grass were propylene mesh + „coladerm“ + chlorhexidine, the mesh not identified. was covered in Georgia Produced biodegradable, biomass 7. Using a new type of prosthetic material has been polymer - „coladerm“7. achieved the reduction of the prescribed periods and con- Results of the clinical studies: Presented „new anti- sequently, economic effects reduced pharmacokinetic septic, biocomposite mesh - minimize the number of com- costs. plications associated with postoperative purulent infection 8. Using a new type of prosthetic material, reducing the and the likelihood of recurrence. New antiseptic, polymer- probability of recurrence, a number of postoperative com- ic meshes are used during the hernioplasty: Reduction of plications and rehabilitation periods have been achieved. treatment costs compared to the standard type of interven- tions; Increase in cost-effectiveness of inpatient care; Phar- maco-economic positive effect; Decrease of treatment timing; Reduction of rehabilitation time. Reduction of the likelihood of recurrence, frequency and rehabilitation of postoperative complications7. This clinical research based on the experimental results once again showed the best anti-microbe features of new antiseptic polymeric biocomposite meshes, without any post-surgery supportive complications7(Figures 3, 4). We conducted detailed analysis in postoperative pa- tients and combined our findings of clinical and experi- mental findings which resulted in developing the practical recommendations of new antiseptic, biodiversity mesh
18 TCM&GMJ, April 2018 Gogoladze et al
Figure 1. Morphological study. The 90th-day histological prep- Figure 2. Morphological study. Colored by hematoxylin- aration. Colored by hematoxylin-eosin. IV regenerative degree eosin . IV regenerative degree
Figure 3. Ultrasound scan. Postoperation period Figure 4. Ultrasound scan. Postoperation period 8 days later 6 month later
References
1. Markov G. Some contemporary aspect in the preventions of the surgical site infections OK Hirurgia. Sofia: 2007; 1-2: 54-9. 2. Yorke Y, McDeavitt K, Martin A, lincourt E, Vertegel A, Heniford T. Mesh Nevel Techniqve involving naturally ocurrrin cellular proteins. Carolinas medical Center. Char-lotte. NC. USA Surg Innov. 2011; 7: 4-8. 3. Guillaume O, Lavigne JP, Lefranc O, Nottelet B, Coudane J, Garric X. New antibiotic-eluting mesh used for soft tissue reinforcement. Acta biomaterialia. 2011 Sep 1;7(9):3390-7 4. Gogoladze M., Chkhikvadze T., Kiladze M., Jikia D. Georgia. Current issues, problems and prosthetics of tension-free hernioplasty (Review) Georgian Medical News, 2014, №7-8 (232-233), pp. 7-12. 5. Gogoladze M., Kiladze M., Chkhikvadze T., Tsivtsivadze L, Jiqia D. Georgia Hernioplastic morphological features (experimental stady). Georgian Medical News, 2016, №5 (254), pp. 73-81. 6. Gogoladze M., Chkhikvadze T., Kiladze M., Jikia D. 1, Georgia . Bac- teriological description of ,,new’’aseptic meshes (Experimental stady). Experimental & Clinicl Medicine, 2016, N5; pp. 36-41. 7. Gogoladze M, Kiladze M, Chkhikvadze T, Jiqia D. Clinical evaluation of the new antiseptic meshes. Georgian medical news. 2016 Dec(261):7-11.
19 TCM&GMJ, April 2018 Moattari et al .
Use of Chitosan/Polyethylene glycol scaffold and Wharton jelly-derived mesenchymal stem cell increases angiogenesis in the damaged sciatic nerve
Moattari M.1 Kaka G.2 Kouchesfahani H.1 Naghdi M.3 Sadraie S.2
Abstract
Introduction: Angiogenesis, the formation of new blood vessels, is necessary in many physiological stages. In this experi- mental study, effects Chitosan/Polyethylene glycol scaffold and Wharton jelly-derived mesenchymal stem cell increase angio- genesis in the damaged sciatic nerve were investigated.
Methods & Materials: In this experimental study, male Wistar rats (n=35, 180-200g) were randomly divided into 5 groups: Control, transected sciatic nerve rats without any intervention; Sham, transected sciatic nerve rats treated with culture medium on the injured nerve; Cs/PEG, transected sciatic nerve rats treated with Cs/PEG membrane around the injured nerve; Cell, transected sciatic nerve rats treated with transplantation of 50000 WJ-MSCs around the injured nerve and Cs/PEG+Cell groups, transected sciatic nerve rats treated with Cs/PEG membrane and transplantation of 50000 MSCs around the injured nerve. Regeneration of sciatic nerve was evaluated using histological analysis, angiogenesis (number of blood vessels and vessel area). Results: At 8 weeks after surgery, the number of vessels in 1000 µm2 increased significantly in Cell and Cs/PEG+Cell group compared to Ctrl and Sham groups (p<0.05). In addition, vessel area percent increased significantly in Cs/PEG+Cell group compared to Ctrl and Sham groups (p<0.05). Conclusion: Chitosan/Polyethylene glycol membrane and Wharton jelly-derived mesenchymal stem cell increase angiogenesis in the damaged sciatic nerve. (TCM-GMJ April 2018; 3 (1):P20-P24)
Keywords: Number of the vessel, vessel area, chitosan, polyethylene oxide, damage, Wharton jelly-derived mesenchymal stem cell, sciatic nerve
and immobilization, idiopathic and progressive, septic and Introduction tuberculous gluteal abscesses, congenital or infantile
ne of the widespread human disabilities belongs (prenatal injuries are thought to be secondary to external to peripheral nerve damage. It is reported that compression from reduced fetal activity, especially when between 13- 23/100, 000 persons/year are de- associated with decreased amniotic fluid, amniotic bands, O voted to peripheral nerve injuries in developing or uterine abnormalities) and non-progressive and un- countries1. According to the reports of a prospective known, post-viral sciatic neuropathy such as herpes zoster study, the most common causes of sciatic neuropathy infection. These types of injuries are not life-threatening injury was varied and included direct trauma, clubfoot but have a great impact on the patients, families and the with unknown mechanism, iatrogenic mechanisms such society2. On the other hand, peripheral nerves have the as various and especially orthopedic surgeries, intra mus- capacity to regenerate after injury but the extent of regen- cular injections, previously a common cause of sciatic eration is not notable. Sciatic nerve injury is most com- neuropathy injury are now uncommon; vascular causes mon experimental model for the study of peripheral nerve (umbilical artery catheterization and following the proce- regeneration due to various reasons such as easily accessi- dure; arteriovenous malformation of the right lower ex- ble, large size, representing mixed motor and sensory tremity and iliac artery stenosis following embolization nerve, and autonomic aspects and huge amount of studies procedures), tumors (giant hypertrophy or plexiform neu- which provide data comparability with previous studies rofibroma of the sciatic nerve because of benign and ma- might explain popularity of sciatic nerve injury model lignant tumors; pelvic neuroblastoma, intraneural peri- among animal models3 . Several approaches also assessed neurioma because of neoplasm or an inflammatory pro- for improvement of peripheral nerve regeneration. As a cess; lymphomas; leukemia, or leiomyosarcomas), and result, cell-based therapies and use of scaffold have been prolonged compression injuries extrinsic compression focused by researchers and clinicians to materials. Hydrogels can provide an exceedingly swollen three From the 1Department of Animal Biology, Faculty of Biological Science, dimensional (3D) environment analogous to soft tissues Kharazmi University, Tehran, Iran.2Neuroscience Research Center, and permit transmission of nutrients and cellular waste Baqiyatallah University of Medical Sciences, Tehran, Iran.3 Fasa University of Medical Science, Fasa, Fars, Iran. through the elastic networks. Based on the origin, they are Received April 04, 2018; accepted April 15 , 2018. categorized into natural and synthetic hydrogels. Synthetic Address requests to: Gholamreza Kaka hydrogels have benefits compared to natural hydrogels, E-mail: [email protected] such as chitosan which is biodegradable, non-toxic/non- Copyright © 2018 Translational and Clinical Medicine-Georgian Medical Journal inflammatory, mechanically similar to the tissue to be re- 20 TCM&GMJ Vol. 3 Issue 1 2018 Moattari et al .
placed, highly and capable of attaching with other mole- Balanced Salt Solution (HBSS) (Gibco, USA), and detach- cules, lasting long enough for axonal regrowth and tissue ing the umbilical cord vessels, the Wharton's jelly cut into repair is preferred4 . Synthetic hydrogels are prepared main- small pieces, centrifuged. The precipitate treated with colla- ly from synthetic polymers (e.g., poly(acrylic acid) (PAA), genase and trypsin, respectively. Finally, 10% FBS-DMEM poly(ethylene glycol) (PEG), poly(vinyl alcohol) (PVA), was added to disperse the mesenchymal stem cells and the polyacrylamide (PAAm)), and polypeptides. Synthetic hy- experimenter counted the cells under a microscope with drogels have emerged as an alternative choice for hydrogel the help of a hemocytometer. It should be mention that scaffolds. Poly(ethylene glycol) or PEG has biomedical the mesenchymal cells were then used directly in the site of applications, such as surface variations, bio-conjugation, injury. To prove stemness and being mesenchymal stem drug delivery and tissue engineering because they have im- cell, at passage 3, the isolated cells were checked by using portant possessions, such as good biocompatibility, non- fibronectin, CD44 and for negative control, CD45 (Santa immunogenicity, and resistance to protein adsorption. Cruz Biotechnology, Santa Cruz, CA) immunostaining10. Cell therapy as a nerve repair strategy creates a favora- 4. Chitosan/polyethylene oxide film preparation ble environment in the peripheral nervous system5. Many Cs/PEG membranes were prepared with a mixture of investigators have been focusing on mesenchymal stem 0.25 g of Cs and 0.08 g Cs/PEG membrane dissolved in cells. In fact, the use of these extraembryonic tissue stem 50 ml of 1% acetic acid solution. The mixture was stirred cell resources has many priorities over other sources be- for two h at 40°C. The resultant solution was centrifuged cause they are a rich source of mesenchymal stem cell and at 2500 rpm for 10 min to prevent air bubbles from form- have exclusive properties such as easy accessibility, few ing. The mixture was cast into plastic Petri dishes with 75 ethical problems regarding their use, wide multipotency, mm diameter, dried at 25 °C for 24 h. The membranes high proliferation rates, hypoimmunogenicity6. The use of were then dried and cut to patches of 1cm × 1cm in size10. treatment with mesenchymal stem cells stem cell improved 5. Surgical procedure axonal regeneration, nerve conduction velocity and im- Animals were anesthetized with 80 mg/kg ketamine prove the motor function recovery7-9. hydrochloride (alfasan, Holland) and 5 mg/kg xylazine hy- The present study aimed to evaluate the effects of drochloride (alfasan, Holland) intraperitoneally. For sciatic Wharton jelly-derived mesenchymal stem cells on Chi- nerve dissection, after the right hind limb was shaved and a tosan/Polyethylene glycol scaffold (Cs/PEG+Cell) regen- longitudinal cutaneous incision was made in the posterol- eration of transected sciatic nerve using histological ateral side of the thigh in length of 3 cm to expose the sci- (angiogenesis= number of blood vessels and vessel area) atic nerve. The right sciatic nerve was then transected at a assessments in a rat model. midway from by a sharp surgical knife. The epineurium was sutured with 7.0 Prolene sutures and the muscle fascia Methods & Materials and skin were then sutured with 4.0 nylon sutures11. 6. Histological analysis 1. Animals For histological assessment, at 8 weeks after surgery, Thirty-five male adult Wistar rats (180-200 g) pur- the sciatic nerves were surgically taken out and fixed 10% chased from Pasture Institute Tehran, Iran (n=7/group) formalin, embedded in paraffin and sectioned at a thick- were used in these experiments. The animals were cared in ness of 5–6 mm. Sections were stained with hematoxylin home cages (n=4/cage) at controlled temperature 23±2°C and eosin for histologic analysis using standard techniques. and 50% humidity with 12/12 h light/dark and have free The number of vessels in 10000 μm2 and vessel area was access to standard rat chow and tap water. All experiments determined by placing an ocular grid over each microscop- involving animals and surgical procedures were approved ic field and counting the number of vessels that fell within by Ethical Committee of Baqiyatallah University of Medi- the grid. Five high power fields were counted for each sec- cal Sciences (The Baqiyatallah (a.s.) University of Medical tion and the average number were counted using MOTIC Sciences Committee on the use and Care of Animals). software (Nikon, Japan, 2001) under light microscopy from 2.Animal grouping at least 5 randomly selected at ×1000 magnification11. Thirty-five rats were randomly divided into five 7. Statistical analysis groups (n=7/group) as below: 1) Control group: transected All data were expressed as a mean ± standard error of sciatic nerve rats without any intervention; 2) Sham group: the mean (SEM). Results were analyzed using one-way transected sciatic nerve rats treated with culture medium analysis of variance (ANOVA) followed by least significant on the injured nerve; 3) Cs/PEG group: transected sciatic difference (LSD) Post Hoc 135 test (SPSS 22.0 software nerve rats treated with Cs/PEG membrane around the package, SPSS Inc., Chicago, IL). A difference less than injured nerve; 4) Cell group: transected sciatic nerve rats 0.05 (P<0.05) level was considered as statistically signifi- treated with transplantation of 50000 WJ-MSCs around the cant. injured nerve and 5) Cs/PEG+Cell group: transected sciat- ic nerve rats treated with Cs/PEG membrane and trans- Results 10 plantation of 50000 MSCs around the injured nerve . 1.Number of vessels in 10000 μm2 3. Preparation of Wharton jelly-derived mesen- At 8 weeks after surgery, the numbers of vessels in chymal stem cell 1000 µm2 were significantly decreased in Ctrl and Sham After collecting the human umbilical cords in Hanks' groups compared to surgical groups (p<0.001). The num-
21 TCM&GMJ, April 2018 Moattari et al . ber of vessels in 1000 µm2 increased significantly in Cell liferation during development and nerve regeneration. These and Cs/PEG+Cell group compared to Ctrl and Sham neurotrophic factors include angiogenic factors of basic fibro- groups (p<0.001)(Figure 1). blast growth factor (bFGF), vessel endothelial growth factor 2.Vessel area (VEGF) and epidermal growth factor (EGF) which are angio- 10 At 8 weeks after surgery, the vessel area was signifi- genic inducers . Nerve growth factor (NGF) is another im- portant angiogenic factor which promotes the neural differentia- cantly decreased in Ctrl and Sham groups compared to tion and survival of several peripheral neurons. Additionally, surgical groups (p<0.001). Vessel area percent increased NGF increases the survival and maintenance of cholinergic neu- significantly in Cs/PEG+Cell group compared to Ctrl and rons and has an important role in neuroprotection of adult rat Sham groups (p<0.001)(Figure2&3). hippocampal neurons. Furthermore, according to some investi- gations NGF has angiogenic effects and nerve growth effects in Discussion several nerve ganglions. Nerve growth factor (NGF) is known as a protein that improves the survival, maintenance during devel-
This study has clearly demonstrated that Chitosan/Poly opment growth, and neurite differentiation of neurons, and ethylene glycol scaffold and Wharton jelly-derived mesenchymal NGF has an important role in nerve regeneration. Moreover, a stem cell increases angiogenesis (number of blood vessels and number of investigations have concluded that NGF is more vessel area) in the damaged sciatic nerve. effective at enhancing angiogenesis rather than neuronal regen- Angiogenesis generally is a key and complex multistep pro- eration10. cess in regenerative medicine, as well as in the specific field of It has been reported that the potential of using Wharton neuronal regeneration. For the first time, Hertig in 1935 used jelly-derived mesenchymal stem cell to improve axonal regenera- angiogenesis which means the formation of new blood vessels tion in peripheral nerve defects are strongly correlated with the from remaining and previous vessels and includes proliferative production of trophic substances. Multiple mechanisms may migration and the differentiation of endothelial cells, the degra- exist in stem cell therapy. Stem cells could help regeneration by dation of extracellular matrix, microtubule formation, and the differentiation into Schwann cells or the release of soluble nerve sprouting of new capillary branches12. growth factors such as brain-derived neurotrophic factor or an- Angiogenesis is important in physiological processes gen- giogenic molecules, including vascular endothelial growth factor eral wound healing and remodeling, growth and development and above mentioned neurotrophic factors10. and repair of organs, embryonic development, organ formation, tissue regeneration, and also female reproduction; menstrual Conclusion cycles. Angiogenesis is known to be essential for wound healing, female reproduction, embryonic development, organ formation, Our results showed that angiogenesis (the number blood tissue regeneration, and wound remodeling12. vessels measured in 10000 μm2 and vessel area) improved signif- There is a relationship between nerve regeneration and icantly in Chitosan/Polyethylene glycol scaffold and Wharton angiogenesis by means of increasing number of large blood ves- jelly-derived mesenchymal stem cell group. sels and changes in capillary number. In fact, with manipulating vascularization, the possibility of nerve regeneration may be enhanced. This is because these increases in angiogenesis pro- Acknowledgment vide a suitable and favorable microenvironment for axons and We thank Prof. Hedayat Sahraei for his kind considera- nerves. In other words, the use of chitosan/polyethylene oxide tions. in accompany with Wharton jelly-derived mesenchymal stem cell improve intraneural blood vessels and enhance nerve regenera- tion after the transaction. Fourteen important neurotrophic factors proteins secreted by mesenchymal stem cells of Wharton jelly which play im- portant role in neuronal survival, angiogenesis, enhancement of the neuronal regeneration by enhancing of integrin and scaffold proteins that anchor cell matrix, Schwann cell viability, and pro-
Figure1: Comparison of the mean number of vessels in 1000 µm2 in Figure2:Comparison of vessel area in all experimental groups all experimental groups (mean±SEM). *** shows that the number of (mean±SEM). *** shows that vessel area increased significantly in Cs/ vessels increased significantly in Cs/PEG+Cell group compared to PEG+Cell group compared to Ctrl and Sham groups at 8 weeks after Ctrl and Sham groups at 8 weeks after surgery (p<0.001). surgery (p<0.001). 22 TCM&GMJ Vol. 3 Issue 1 2018 Moattari et al .
12.
A B
C D
E F
Figure 3: (A) Ctrl group, (B) Sham group, (C) Cs/PEG group, (D) Cell group, (E) Cs/PEG+Cell group. Magnification ×100. (F) The arrow shows a blood vessel with red blood cells, interrupted arrow shows the nucleus of an endothelial cell. The number of vessels in- creased significantly in Cs/PEG+Cell group compared to Ctrl and Sham groups. Hematoxylin and eosin staining. Magnification ×1000.
23 TCM&GMJ, April 2018 Moattari et al .
References
1. Rosberg H-E, Carlsson KS, Cederlund RI, et al. Costs and outcome for seri- ous hand and arm injuries during the first year after trauma–a prospective study. BMC public health 2013;13:501 2. Rosberg H-E, Carlsson KS, Cederlund RI, et al. Costs and outcome for seri- ous hand and arm injuries during the first year after trauma – a prospective study. BMC Public Health 2013;13:501-501 3. Geuna S, Raimondo S, Ronchi G, et al. Chapter 3 Histology of the Peripheral Nerve and Changes Occurring During Nerve Regeneration. In: Stefano G, Pierluigi T, Bruno B, eds. International Review of Neurobiology: Academic Press; 2009:27-46 4. Elmstedt N. Development of biosynthetic conduit for spinal cord and periph- eral nerve injury repair, in vitro study. Thesis. Stockholm, Sweden; 2006 5. Peng J, Wang Y, Zhang L, et al. Human umbilical cord Wharton's jelly- derived mesenchymal stem cells differentiate into a Schwann-cell phenotype and promote neurite outgrowth in vitro. Brain research bulletin 2011;84:235- 243 6. Troyer DL, Weiss ML. Concise Review: Wharton's Jelly‐Derived Cells Are a Primitive Stromal Cell Population. Stem cells 2008;26:591-599 7. Yarar E, Kuruoglu E, Kocabıcak E, et al. Electrophysiological and histo- pathological effects of mesenchymal stem cells in treatment of experimental rat model of sciatic nerve injury. International journal of clinical and experi- mental medicine 2015;8:8776 8. Guo Z-y, Sun X, Xu X-l, et al. Human umbilical cord mesenchymal stem cells promote peripheral nerve repair via paracrine mechanisms. Neural regenera- tion research 2015;10:651 9. Pereira T, Gärtner A, Amorim I, et al. Promoting Nerve Regeneration in a Neurotmesis Rat Model Using Poly (DL-lactide--caprolactone) Membranes and Mesenchymal Stem Cells from the Wharton’s Jelly: In Vitro and In Vivo Analysis. BioMed research international 2014;2014 10. Moattari M, Kouchesfehani HM, Kaka G, et al. Chitosan-film associated with mesenchymal stem cells enhanced regeneration of peripheral nerves: A rat sciatic nerve model. Journal of chemical neuroanatomy 2018;88:46-54 11. Sadraie SH, Parivar K, Arabi F, et al. Study of Transected Sciatic Nerve Re- pair by Amniotic Membrane with Betamethasone in Adult Albino Wistar Rats. Archives of Iranian Medicine (AIM) 2016;19 12. Mousavi M, Baharara J, Zafar-Balanezhad S, et al. The effect of saffron aqua extract on angiogenesis in chick chorioalantoic membrane. Zahedan Journal of Research in Medical Sciences 2014;16:55-58
24 TCM&GMJ, April 2018 Chigogidze et al.
Gender differences in coronary collateral circulation during acute
and stable ischemic heart disease
Chigogidze M.1 Sharashidze N.1 Paghava Z.2
Abstract
Background: Diseases of the cardiovascular system are seen in the whole world as the main cause of death. In women, heart attack and stroke are associated with twice increased mortality rate. Collateral blood vessels during the coronary artery disease represent an alternative source of myocardial blood circulation. They reduce the infarction area, improve the functioning of the
heart, avoid development of a ventricular aneurysm. The sex-related differences in patients with ischemic heart disease in rela- tion to the anatomy of coronary blood vessels have been established. However, the existence of gender differences in relation to the coronary collateral circulation and its determining factors is unknown. Method: We have used PubMed and Google Scholar medical databases and retrieved the articles for the last 10 years, contain- ing the following keywords: Coronary artery disease, Ischemic heart disease, Human coronary collateral circulation, Vasculo- genesis, Angiogenesis, Gender differences in coronary collateral circulation. Conclusion: There was not detected any credible research in terms of gender differences in coronary collateral circulation, which is a pressing issue and is still a subject of research, in the scientific articles, searched for by us in Pub-Med and Google Scholar medical databases for 2006-2016. (TCM-GMJ April 2018; 3 (1):P25-P31)
Keywords: Coronary artery deasease, Ishcaemic heart disease, Human coronary collateral circulation, Vasculogenesis, Angio- genesis, Gender differences in coronary colatteral circulation.
Urgency of Problem tional collaterals in the atherosclerotic coronary obstruc- ardiovascular diseases (CVD) are considered as tion in vivo was not documented until 200319. the main cause of death in the world at present. About half of the deaths caused by non- C contagious diseases come for cardiovascular Coronary Collateral Circulation, Physiology, Classifi- diseases. Experts estimate that this number will reach cation 23.6 million by 20301,2. Heart attack and stroke in women Coronary collateral arteries have been referred to as are associated with the twice increased mortality rate. end-arteries for decades. Currently, they are known as About 3,4 million women die in the world with ischemic relevant vascular anastomosis that connects the epicardial heart diseases per year.3 coronary arteries and represents the alternate source of Historical issues myocardium at the occlusion of main coronary blood ves- sels. They preserve the contractile function of the myo- In 1669, Hens first described the existence of anasto- cardium. Their growth is initiated by ischemia, although mosis between the right and left coronary artery, and in collaterals are also found in individuals who do not have a 1757 the Swedish Albert Von Haller described the coro- coronary artery disease. The pilot studies have demon- nary anastomosis structure. However, the decisive role strated the impact of such external factors on their devel- was not attributed to them in patients with CAD till the opment, like the growth factor, granulocyte colony stimu- 10,11 middle of the 20th century . In 1912, James Herik de- lating factor (G-CSF)20,21,22. In some patients, the collat- 15,16 scribed coronary thrombotic obstruction in the pres- eral flow is sufficient for the normal functioning of heart 12,13,14, ence of interoceanic anastomosis which evidenced in the resting condition but not during exercise23,24. Also, that coronary collateral circulation is a significant deter- there is an opinion that collaterals may not prevent myo- minant of the size and quality of myocardial cells. At the cardial ischemia in the coronary occlusion. For the pre- same time during, percutaneous coronary intervention in vention of myocardial ischemia in case of acute occlusion vivo coronary collateral measurements (PCI) was first of blood vessels 20 to 25% of flow have to reach myocar- 17,18 performed in the late 1970s . The existence of func- dium25. One of the four patients without CAD has enough collateral circulation, while in the patients with 1 From the Ivane Javakhishvili Tbilisi State University; Faculty of Medicine , 26 2Center of Vascular and Heart Diseases Named after Acad. N. Bokhua CAD the same index is one from three . The reason for Received November 30, 2017; accepted March 04, 2018. this is unknown, although there is an opinion on the im- Address requests to: Maia Chigogidze E-mail: [email protected] portant role of genetic factors27,28. Copyright © 2018 Translational and Clinical Medicine-Georgian Medical Journal
25 TCM&GMJ Vol. 3 Issue 1 2018 Chigogidze et al. Physiology of development of collateral blood circula- collaterals, as the free (open) coronary artery increases tion (Arteriogenesis) back pressure in the collateral irrigation area and gradually reduces the degree of damage43. The visual method has The most important trigger (which is also referred to certain restrictions: there is no strictly objective evaluation as arteriogenesis) for collateral development is the indirect method, affects pressure and contrast flow during injec- and variable stress on the endothelial cycle, which in paral- tion during angiography. The second method of measuring lel is occurring in the bone marrow where the mononucle- is known as collateral flow index (CFI). 2 methods are ar cells are worked out29. In case of the main artery ob- available: First - is based on the Doppler velocity measure- struction or occlusion, the pressure gradient is developed ment, which is limited due to frequent artifacts. And sec- in the place of collateral anastomosis30,31. It is a driving ond, more sophisticated considers pressure measurement. force and increases blood circulation in the collateral arte- The simplest, cheaper, and most efficient method of meas- rioles, strengthens the vascular resistance, activates the uring the collateral function is the intracoronary ECG. endothelial of collateral arteriolls32,33. This process does All three methods (Rentrop score, CFI, and intracoro- not depend only on the patency of mechanosensory chan- nary ECG) are needed and represent the predictive clini- nels and the endothelial surface. The cellular response is cal solution44. There is another method of assessment, very important.34 The cytoplasm and endothelial glycopro- known as the washed collaterometer, which is determined tein, get involved in the process35,36. Cationic channels, on by the time when distal collateral is filled with contrast the surface of cells, with their mechanical receptors and substances. According to this method, the best collateral is intercellular molecules (intercellular adhesion molecule 1 washed more quickly45. (ICAM1), vascular cell adhesion molecule 1 (VCAM1) promote adhesion of circulating mononuclear cells and Physiological Mechanisms of Collateral Circulation intermediate metabolites such as (NO) and other pro- arteriogenic molecules. All of the mentioned lead to endo- A range of researchers has been conducted in order to thelial activation and collateral proliferation, after which clarify the physiological mechanisms of collateral circula- protein 1 is released37. The synthesis of NO occurs in the tion (Vasculogenesis, Angiogenesis, and Arteriogenesis). endothelial cells (NOS2 and NOS3) and it promotes not The role of coronary angiogenesis is important in the only the vasodilation but the proliferation of collateral ar- course of ischemic heart disease46,47,48. Coronary collateral teries as well38,39. The involvement of monocytes in this circulation preserves myocardial viability and functioning process, their circulation, and migration in endothelium of the heart muscle. On the other hand, the risk of neuro- enhances the activation of metalloproteinase (MMPs), the vascularization of atheromatous plaque is developed, matrix product of cytoplasm, which is a factor of arterial which eventually ends with its destabilization and exclu- remodeling. Finally, we get development and growth sion. That is why the study of the role of angiogenesis in (angiogenesis) of the collaterals, new capillary vessels in- the patients with ischemic heart disease is necessary49,50,51. duced by ischemia. Their growth is promoted by the pres- sure gradient between the proximal part of the blood ves- Growth Factors (Angiogenesis and Arteriogenesis) sel and site of the coronary stenosis. Endothelial cells Angiogenesis is a well-regulated cascade reaction pro- stimulate nitric oxide and MCP_1, monocytes that play a cess, with the participation of growth factors, that eventu- major role in collateral remodeling are involved in the pro- ally lead to a proliferation of endothelial cells in the new cess41. vascular network. Newly formed capillaries can restore It is important that the collaterals are often regressed effective perfusion only of a small area46,47. As soon as the reason is eliminated. The mentioned pro- Arteriogenesis is a complex process involving a large cess is referred to as “pruning”40. number of different types of cells and growth factors as a result, large blood vessels are formed, with the well- Evaluation of Coronary Collateral Circulation, Classi- developed media that promote restoration of the necessary fication effective perfusion, which in turn is the therapeutic goal of There is no technical and quantitative method of non- angiogenesis47. Development of collateral circulation is a invasive evaluation during chronic total coronary occlu- significant result of arteriogenesis in chronic coronary ar- sion. Evaluation is done visually with coronary angi- tery disease. Interaction of different factors and their in- ography, which is known as the semi-quantitative method. volvement in the process of angiogenesis is not fully stud- It was described by Rentrop et al42 and implies the balloon ied. occlusion of the contralateral coronary artery. Collaterals Significant growth factors include: from the occlusion area are classified as follows: a) Vascular endothelial growth factor (VEGF) that grade 0-no collaterals; enhances migration and survival processes of endothelial grade 1-side branch filling of the recipient artery with- cells, products of the plasminogen's activator and intersti- out filling of the main epicardial artery; tial collagens, as well as the migration of plain muscle. grade 2-partial filling of the main epicardial recipient b) Transforming growth factor (TGF- β), promotes artery; the transformation of fibroblasts and stimulation of prolif- grade 3-complete filling of the main epicardial recipi- eration by activation of fibrosis processes. ent artery c) Fibroblast growth factor (FGF) - Stimulates cell It should be noted that most clinicians and researchers proliferation and migration of embryonic mesodermic and evaluate the Rentrop classification without occlusion of neurotoxic origin 26 TCM&GMJ, April 2018 Chigogidze et al. d) Inhibiting angiogenesis factor – endostatin-heparin al Patients with chronic angina, who have recently suffered connecting fragment - Specifically inhibits endothelial cell from acute myocardial infarction, were compared to pa- proliferation, thus inhibiting angiogenesis (Scheme 1)46,47. tients with newly emerged angina and an acute myocardial Arteriogenesis is the process of transformation of infarction57. For the last one year, they had a high risk of the earlier (collateral) arterial to functional (muscular) col- death rate and reinfarction. Based on the mentioned the lateral artery48,49,50. myocardial ischemia was named as the grounded stimula- The definition of Angiogenesis is used to determine tor for the development of coronary collaterals57. the formation of new capillaries, which will emerge from the pre-existing post-capillary venules51. the further growth and remodeling of these vessels to the complex vascular Eosinophilia network is referred to as angiogenesis52. Vasculogenesis involves the growth processes inside Monocytes, neutrophils, lymphocytes and vascular the blood vessels when the endothelial cells migrate to growth factors (such as endothelial growth factor, fibro- various locations, they gather and produce endothelial blasts growth factor and transformational growth factor chords, and then form the endothelial tubes52. Thick mus- [TGF-β]) play an important role in the development of cle membrane is necessary for the vessel to acquire vasoe- coronary collateral blood circulation, however, they can lastic and vasomotoric52,53. not fully explain the development of the mechanism of the Collateralization in patients is different. In healthy coronary collateral blood circulation63. individuals, it is correlated with hypertension and de- There are few studies on the relation of coronary ar- pressed heart rate, while there are variable on correlations tery disease and eosinophilia. According to a study by between severity of coronary artery disease and coronary Jiang et al, it is described that low levels of eosinophils are stenosis, duration of angina pain, vascular proximal locali- associated with serious myocardial damage and that eosin- zation damage and long-lasting occlusion in the pa- ophils play an important role in thrombosis in patients 54,55 tients . with the acute coronary syndrome64. According to the re- Pressure gradient and shear stress search of Toor et Al, eosinophils are new biomarkers for risk stratification in patients with CAD, which was initially The mediators of the processes of arteriogenesis are associated with reduced mortality but after 6 months with the increased pressure gradient and shear stresses. During increased mortality65. the hemodynamically significant stenosis of the main ar- Eosinsofiles are considered as an important source of tery the pressure gradient, which promotes the formation TGF-β1, which may serve as the modulator of the appro- of collaterals, is developed. Distally of the stenosis blood priate response during the acute phase66. According to the pressure is low. The blood flow will be distributed in the research conducted in China in 2008-2014, the correlation existing arterioles that connect the high-pressure area with between eosinophilia and coronary collateral circulation the low-pressure area. This leads to the increase in flow was detected in 502 patients with unstable angina. It was rate and shear stress in the existing collateral arteries, found that EOS was associated with and could inde- which in turn result in the endothelial activation, advances pendently predict high-grade CCC in patients with UAP in the growth monocyte adhesion and their transformation with epicardial coronary arteries stenosis 80%67. The re- into the macrophages. This eventually leads to morpholog- gressive analysis has shown that the specified quantity of ical changes and remodeling52,53,55. eosinophils (odds ratio: 1.969; 95% confidence interval [CI]: 1.210–3.205; P=0.006) and neutrophils (odds ratio: Myocardial Ischemia 0.757; 95% CI: 0.584–0.981; P=0.035) are independent predictors of coronary collateral circulation. Eosinophils in Myocardial repeated ischemia is a stimulating factor quantities of 0.12×109/l can independently be the predic- for the development of coronary collateral circulation55. In tors of high-quality coronary collateral circulation with the process of angiogenesis, occurring in response to the 72,5% probability and 58.4% specificity 68 Coronary collat- hypoxia, other mechanisms are also involved, though eral circulation and epicardial coronary collaterals normally there is the opinion that the development of collaterals are not visualized on the angiogram until the coronary ar- through the arteriogenesis does not depend on the is- tery stenosis reach 80%, when the pressure is reduced and chemia55. Collateral arteries may be developed in the non- the coronary collateral circulation becomes noticeable. hypoxic tissue. While angiogenesis is induced by hypoxia, Inflammatory mediators, monocytes, neutrophils, lympho- arteriogenesis is induced by shear stress. Both, chemokine- cytes, cytokines play an important role in the formation of sis and growth factors are involved in the process, though coronary collateral circulation69,70. in different ways. Factors TGF-α, VEGF, b-FGF induce Jiang et al suggest that the reduced number of eosino- Angiogenesis and proliferate the endothelial cells; while phils indicate severe myocardial infarction, eosinophils the factors, like TGF-β, GM-CSF, b-FGF, which stimu- play an important role in forming thrombosis during acute late arteriogenesis, proliferate smooth (plain) muscle53,54,55. coronary syndrome. According to the study of Verdoia et According to the research by Takeshita et al In case of the al number of eosinophils is higher in patients with well- recurrent myocardial ischemia, when a vascular occlusion developed collateral circulation compared with patients occurs, collaterals begin functioning instantly, while in a with poorly developed coronary collateral blood circula- state of rest they are inactive56. According to the Herlitz et tion. Eosinophils play an important role in inflammatory 27 TCM&GMJ Vol. 3 Issue 1 2018 Chigogidze et al.
response regulation in patients with unstable angina67. does not fully reflect the changes that are developed in Finally, it is suggested that eosinophilia may be an inde- case of acute coronary occlusion and thus can not be com- pendent predictor of high-quality coronary collateral circu- pared to the same changes in the chronic coronary occlu- lation in patients with unstable angina in case of the steno- sion93. The positive effect of the collateral circulation on sis of 80% of epicardial coronary arteries71,72,73,74,75. the outcome of patients who have been subjected to the mechanical intervention in the first hours of acute myocar- dial infarction is not still fully investigated. In the study Collateral Circulation, Reserve of Coronary Flow and conducted with the participation of 1,164 patients 6 Its Prognostic Significance months death rate was low in patients with coronary col-
lateral, compared to patients with no collateral (4% vs 9%, Collateralization in patients is different. Years ago there p = 0.011), was an opinion that the ischemia was the basis for the de- After multivariate analysis, CC did not emerge as a sig- velopment of collateral circulations. However, studies did nificant variable in relation to 6-month clinical and angio- not prove this fact20. Structurally coronary collaterals were graphic outcomes. CC does not exert a protective effect in found in 80% of newborns, indicating vasculogenesis in patients who undergo mechanical intervention in the first the embryogenesis. Coronary circulation in humans has a 6 hours of AMI onset 94. wide network of the anastomosis, even when the coronary
artery disease is not formatted. Eventually, in case of ne- Gender Differences, What Makes Gender Aspect In- cessity, they will transfer into coronary collaterals and can teresting? prevent signs of myocardial ischemia in the short-term
coronary occlusions in ¼ of individuals58. There are varia- Cardiovascular disease develops 7 to 10 years later in ble data on the links between the severity of the coronary women than in men and is still the major cause of death in artery disease and the severity coronary stenosis, the lesion women. The risk of heart disease in women is often un- of proximal localization and the long-term occlusion in the derestimated due to the misperception that females are patients20. It is known that the correct functioning of col- ‘protected’ against cardiovascular disease. The under- laterals is associated with low frequency of heart rate and recognition of heart disease and differences in clinical absence of arterial hypertension. Along the development presentation in women lead to less aggressive treatment of the disease of coronary arteries, well-developed coro- strategies and a lower representation of women in clinical nary collaterals reduce mortality in patients58. The protec- trials. Over the past 2 decades, MI prevalence has in- tive effect of coronary collaterals in case of acute myocar- creased among midlife women, while declining among dial infarction is represented in the following way: decreas- similarly aged men. Also, although the risk of future hard ing infarction zone and fatal arrhythmias (such as arrhyth- cardiovascular events remains higher in midlife men com- mias with extended QT intervals); improving left ventricu- pared with midlife women, the gap has narrowed in recent lar function and preventing of an aneurysm92. As we face years. Greater emphasis on vascular risk factor control in difficulties in evaluating the collateral blood circulation, midlife women might help mitigate this worrisome studies have shown the opposite prognostic significance of trend97,98. collateral fertility. Their high impact on mortality is still Women in their midlife years have historically been at a controversial92. Few studies, reflecting the effect of the lower risk for overall vascular events than similarly aged collateral circulation on mortality, have been conducted up men. We recently reported, however, that in a nationally to now. Only 3 of them clearly reflect the advantages of representative sample of the US population that participat- collateral blood circulation. The disparity is still a subject ed in the National Health and Nutrition Examination Sur- of discussion. This is partially explained by the method of veys (NHANES), self-reported stroke prevalence among evaluation of collateral blood circulation used in most women aged 45 to 54 years was double that of similarly studies. The collateral is assessed visually by coronary angi- aged men99,100. ography, while the use of intracoronary flow or pressure It is often argued that women have smaller coronary measurement method (collateral flow index) with the arteries, coronary circulation, and thus worse coronary Doppler is more accurate20. outcomes, simply because their bodies are smaller. The The significance of the collateral circulation in chronic results of this investigation Stuart and Co-authors reaf- total occlusion of the coronary artery, with the preserva- firm that body size is positively correlated with coronary tion of the left ventricular function, is vivid. There are also artery size and collaterals101. Many of the major studies of some examples of patients with the occlusion of a left cor- vessel dimensions discussed, including the previous Intra- onary artery or three-vessels and light symptoms correla- vascular ultrasound investigation, found that after correct- tion between collateral and restenosis is also investigated20. ing for body or heart size, sex differences lost statistical Clinical trials confirm rapid regression of collaterals fol- significance. lowing the PCI in chronic total coronary occlusion. The mechanisms that underlie the sex difference are Coronary collaterals are also developed with the higher unknown. It may be because of differences in levels of degrees of coronary occlusion. A study has been conduct- hormones that control vascular tone and size101. ed to demonstrate the existence of latent coronary collat- The rates of collateralization between men and women eral in humans.They start functioning immediately after remain unclear and there are few studies concerned with coronary obstruction. Despite the changes in time, the way gender differences in coronary collateral circulation in collateral change under the coronary collateral pressure 28 CAD patients. Shi Lui and co-authors investigated 868 TCM&GMJ, April 2018 Chigogidze et al. patients with obstructive CAD. Patients were assessed for Referencs collateral grades based on the Rentrop grading system, Overall, 53% of participants had collaterals. Difference 1. World Health Organization, Media Center - 10 Major Causes Of Death between sex groups was found. Men had higher rates of Http://Www.Who.Int/Mediacentre/Factsheets/Fs310/ collaterals than women (P-value = 0.000175)102. 2. Ministry Of Labor, Health And Social Affairs Of Georgia, National Center For Disease Control And Public Health - Statistical Reference (2009-2013) Some studies showed that there was no significant ef- 3. Health Care-Brief Statistical Overview (2015) Http://Www.Ncdc.Ge/ fect of sex on collateral vessel development103. In a study Attachedfiles/Highlights_GEO_FINAL_D0f04f97-E374-4eeb-8770- conducted by Tahiti E and co-authors eighty-four of the 32cbb0a25a84.Pdf 4. Ministry Of Labor, Health And Social Affairs Of Georgia. National Health 1236 patients who had acute myocardial infarction and Report - 2013-2014 total proximal occlusion in only the left anterior descend- 5. Health System Performance Assessment Report 2013 Http:// Www.Healthrights.Ge/Wp-Content/Uploads/2013/01/Jandacvis- ing coronary artery (LAD) or the right coronary artery Sistemis-Efekturobis-Angarishi.Pdf (RCA) were selected. 74 patients were included (49 men, 6. World Health Statistics 2010http://Apps.Who.Int/Bookorders/Anglais/ 25 women) in the study. None of the patients had reperfu- Detart1.Jsp?Sesslan=1&Codlan=1&Codcol=15&Codcch=56 7. Lloyd-Jones D, Adams RJ, Brown TM, Carnethon M, Dai S, De Simone sion criteria (ie, decrease in early ST elevation and reperfu- G, Ferguson TB, Ford E, Furie K, Gillespie C, Go A. Heart Disease And sion arrhythmia). In this study, factors such as age, sex, Stroke Statistics—2010 Update. Circulation. 2010 Feb 23;121(7):E46-215. BMI, HT, and smoking did not have a significant effect on 8. Heberden W. Some Account Of A Disorder Of The Breast. Med Trans Call Physns Lond. 1772;2:59-67. 8.Baron J. The Life Of Edward Jenner CCV development103. However, others showed that in MD. Cambridge University Press; 2014 Mar 20. acute coronary syndrome men tended to develop greater 9. Black S. Clinical And Pathological Reports. 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To fill the missing fragments of a complex mosaic of liver regeneration
Tsomaia K.1,2 Inauri N.1 Patarashvili L.1 Karumidze N.1 Azmaiparashvili E.1 Bebiashvili I.1
Kordzaia M.2 Kakabadze M.2 Dzidziguri D.1 Kordzaia D.1,2
Abstract
Background: Liver resection has increased due to the increased number of liver pathologies and frequency of transplan- tation of the half of liver from living donor. New Surgical approaches allow removal of massive space-occupying hepatic tu- mors, which earlier was considered as inoperable. Liver regeneration after its resection is one of the most intensively studied processes. It’s a paradox, that in existence of such large number of studies regarding the mechanisms of liver regener- ation, structural side of liver’s remnant growth following partial hepatectomy (PH) is practically less researched, and the questions - “How the structure and architectonics of regenerated liver differs from normal, regular liver? “ still waiting for an- swers. Method: We have reviewed the articles of the last two decades from PubMed and Google Scholar medical databases contain- ing in the advanced search engine “title/abstract” at least 2 keywords from the following: Liver regeneration, partial hepatec-
tomy, living donor liver transplantation, liver histology, immunohistochemistry, stem cells. The additional articles were ad- dressed in case of underlined contextual necessity. Conclusion: To fill the gaps of our knowledge in the structural changes of liver regeneration after PH, it should be found out: What happens with liver lobules? Is enlargement of liver remnant after PH is caused by the development of new lobules or increase in the volume of existed ones? How do the branches of the tubular (vascular) structures “follow” liver’s growth – by “developing of new branches” or “extension/elongation” of old ones? What are the differences between architectonics of normal and regenerated liver? The existence of such questions proves the importance of further investigation of liver regeneration to fill the missing fragments of the complex mosaic of liver regeneration, without which it is impossible to imagine this process in whole. (TCM-GMJ April 2018; 3 (1):P32-P37)
Keywords: Liver regeneration, partial hepatectomy, liver histology, stem cell, liver donor
Background – in the U.S. in 1988-2018.01.31, 170 965 liver transplanta- tion was conducted, including 6406 from living donor. At he need for liver resection has increased present, the number of officially registered persons in line over the last two decades due to the in- for liver transplantation comprises several thousand. How- creased number of liver pathologies on the ever, considering the frequency of viral hepatitis and its T complications as well as liver cancer, the number of pa- one hand, and increased the frequency of trans- plantation of part of the liver from living donor, on the tients needing liver transplantation, accounts for several other1. million by estimation. New Surgical approaches, such as extracorporeal re- The successful functioning of both - resected as well as section of the liver with further autotransplantation transplanted liver halves depend on the unique regenera- (replantation) of the residual liver using temporary porto- tion ability of liver. Liver regeneration after its resection is caval shunt2 and/or Associating Liver Partition and Portal the one of the most intensively studied processes7–19. vein ligation for Staged hepatectomy - ALPPS3–6, allow This is highly supported by the fact that various removal of massive space-occupying hepatic tumors, modifications of liver resection are easily modeled in which earlier was considered as inoperable. experimental studies, especially in small laboratory animals According to the United Network for Organ Sharing (rodents)19–24. It is experimentally proven that on 7th-8th days 1 From the Department of Clinical Anatomy and Operative Surgery, Faculty (according to some authors, on the end of the 2nd week) 2 of Medicine, Ivane Javakhishvili Tbilisi State University (TSU); TSU, Al. after the liver resection (partial hepatectomy – PH), liver Natishvili Institute of Morphology regains its size and mass almost completely25. Received February 12, 2017; accepted March 11 , 2018. Address requests to: Keti Tsomaia E-mail:[email protected] The study of post-resection liver regeneration phenom- Copyright © 2018 Translational and Clinical Medicine-Georgian Medical enon involves: Journal research of triggers and stimuli of regeneration26;
32 TCM&GMJ Vol. 3 Issue 1 2018 Tsomaia et al. research of molecular pathways of regeneration and mitoses activation), while, complete extraction of the liver its termination after the liver mass is restored26; caused acceleration of second animal’s liver regenera- research of structural changes (cellular and tissue) dur- tion48,49. In this case, it is clear that the above-mentioned ing regeneration process27; factors and NO are excreted by the remained liver which It is shown that PH causes activation of mitosis in intramural portal system receives the blood from the portal hepatocytes, which initiation is related with the complexity circulation of both animals with increased pressure and ac- of the mechanism including the signaling pathways con- celerated flow. It was also shown, that orthotropic trans- trolled by mitogenic growth factors and their receptors, plantation of liver from small size donor to larger size re- multiple cytokines and other signaling molecules that initi- cipient causes the increase in transplant’s size50. In vice ated DNA synthesis in hepatocytes 9,11,12,15,16,28–32. versa, the liver transplantation f r o m the large to small Majority of authors assume that during liver resec- animals causes the reduction of the graft size51. tions, growth factors and cytokines are produced as a Thus, based on our own experiments and literature result of damage to liver tissue (matrix and cell popula- review, we believe that the role of triggering stimulus of tion)33. But unlike humans, excision of one or more lobes liver regeneration is played by portal hypertension sharply in the laboratory animals, whose liver is built from inde- developed after PH as a result of extraction of a large pendent lobes, requires the only ligation of appropriate mass of liver (2/3 and more) leading to the acute reduc- blood vessels. Thus, damage to the parenchyma of the tion of the intramural portal network. part which has to be removed, as well, as the one, which However, in conditions of portal hypertension, pres- remains, is minimal34. Due to this fact, post-resection sure increases not only in sinusoids, covered by fenestrat- regeneration of liver in rats is considered as a classical ed endotheliocytes52 but in spaces of Disse as well, model of regeneration35,36. which hosts various types of cells (Ito, Kupffer cells) also It is confirmed that portal hypertension and intensity involved into the production of signaling molecules and of liver tissue regeneration correlates with the resected factors regulating liver regeneration30,38,39,53,54. mass of liver37–39. After PH the portal blood pressure is Of course, regeneration mechanism developed after the increased because the portal blood receiver - total volume loss of large functioning mass of liver via other methods of the intrahepatic portal network consisting with intrahe- (CCl4, D-galactosamine or acetaminophen poisoning for patic portal vein branches and sinusoids - is smaller in instance) can (should) be different and progressed by active remnant liver comparing to the whole liver before resec- involvements of the stem (progenitor) cells11,34,55,56. tion. Data about the mechanisms terminating liver regenera- This fact supports the assumption that the hepatocyte tion after PH is relatively rare and therefore less clear. In mitoses are stimulated by the growth factors and differ- addition, the consensus exists on the fact that liver contin- ent signaling molecules that are generated after PH not ues to regenerate until it reaches its original size, enough to as much due to the mechanical damage of liver tissue, meet body’s demands11,13,29,35,57–60. but due to the changes in blood vessels, resulted from As a result of compilation our own experiments and increased pressure and accelerated blood flow literature, we believe that liver regeneration, most proba- (development of “share stress” in sinusoids, which leads bly, will be ended, as long as, due to the “growth” of liver excretion of endothelial factors and NO in blood circu- tissue and “increase” of the intrahepatic portal network, lation)40–44. pre-operational characteristics of portal circulation will be The relation among portal hypertension following PH restored. This assumption is proved by the results of and the initiation of hepatocytes’ mitoses was confirmed those experiments, which implied the transplantation of by our experiments: in the male rats, a sharp increase in liver from puppy to adult animal. The intrahepatic portal portal pressure was observed immediately after PH, network of the puppy was able to pass portal blood of caused by the sharp decrease in volume of the intrahepat- adult animal only in conditions of increased pressure and ic portal network. Increase in portal pressure was also flow. As a result, the increase of liver size (regeneration), confirmed by spleen enlargement and widening of extra- was observed despite the fact, that puppy’s liver was not hepatic tributaries of the portal vein. Portal hypertension subjected to the resection. Growth ("regeneration") pro- was accompanied by early response genes (ERG) expres- cess was halted only when the portal hemodynamic was sion and wave-like increase in hepatocytes’ mitoses32,45. back to the pre-operational parameters50. In addition, if PH was performed after spleen vein Thus, we can summarize that liver regeneration, as shunting with vena cava inferior, or after the preliminary well as its termination, is regulated by the complex of performed porto-caval shunt providing invariability of pre- molecular-biological and biochemical processes, triggered operation portal blood pressure and flow in the liver tis- by the acute development of portal hypertension follow- sue remained after PH (the same volume of blood gets ing PH. through portal vein to liver remnant, as before the opera- In spite of the increased number of studies devoted to tion in same tissue of liver), the delay of hepatocytes’ liver regeneration, not rarely, because of the controver- mitoses and liver regeneration was observed46,47. sial data, the number of questions is rising. Discovery of In those experiments, where portal systems of two each new participant of the process (factor, signal, genes, animals were connected with the shunt, PH of one animal etc.) makes it even more difficult to present above- caused the increase in the size of another’s liver (through mentioned complex in a whole and reaching consensus on
33 TCM&GMJ, April 2018 Tsomaia et al. mechanisms of liver regeneration after PH11. In addition, it should be noted, that meaningful part It’s a paradox, that in existence of such large num- of the researchers suggesting different mechanism for ber of studies regarding the mechanisms of liver re- liver regeneration after PH are conducted on “knockout” generation, structural side of post-PH liver growth is mice14,72–76 and/or on the different terms after interven- practically less researched, and the questions - “What is tion but not on the “normal” (not “knockout”) and in a the construction of regenerated liver? How it differs permanent regime, that can be a cause of different inter- from normal, regular liver? “ still waiting for answers. pretations. The elaboration of the standardized view on As a result of the literature review, the impression is the structural transformation after PH is complicated by that researchers intensively research triggers of regenera- the supposition that various processes as are cells hyper- tion and mechanisms (searching the answers on the fol- trophy, proliferation, transdifferentiation, incomplete divi- lowing questions: “What is the reason” and “How”) and sion (polyploidy hepatocytes including binuclear ones), post-regenerative changes (answers on question “What do may replace each other in the dynamics of liver regenera- we get after regeneration?”) still remains outside the focus. tion27,28,32,36,77–79. However, with the availability of resources for the During the last year, the number of works indicating structural research and correct planning of experiments the participation of bone-marrow derived 10,80 or liver stem (right design), the dynamics of structural changes cells (oval cells) in liver regeneration, is increased 8,10,16,81– (restoration) of the liver after PH is solvable more easily in 85. reality (in contrast to the molecular-biological and bio- The recent data have reported that infusion of homolo- chemical mechanisms of regeneration). gous stem cells in the intact part (lobe) of the liver during Review of the literature illustrates that the majority of the expansive liver resection, against the background of authors confirm proliferation of hepatocytes after PH the portal vein ligation of the damaged part, leads to more 8,12,15,18,54,61–63. However, the studies of other cell popula- rapid and more significant growth of the in future liver tions are less and poorly systematized. There are only a remnant, than it occurs only in the conditions of portal few studies that indicate the activation of DNA synthesis vein occlusion and/or partial hepatectomy 86,87. The same in all types of liver cells during the PH12,40,64, but several data are confirmed in terms of APPLS6. Considering that authors deny proliferation of the endotheliocytes, covering in-vitro formation of such three-dimensional structure of the sinusoids52, which in turn raises a question of how the the liver bud from the endodermal, mesenchymal and en- growth of sinusoid networks “follow” the growth of liver dothelial pluripotent stem cells, which have the ability to mass? Do the endotheliocytes subjected to hypertrophy? be involved in in-vivo hemocirculation had been intro- This assumption has right to exist, given that some au- duced86, the "re-visit" of the morphology of regeneration, thors instead of hepatocyte proliferation, after PH, de- following the intraportal infusion of the stem cells in the scribe hepatocyte hypertrophy65 and/or presence of both intact lobe of the liver, in case of ALPPS, becomes im- of the processes at the same time36,66,67. In addition, hy- portant. pertrophy is developing immediately after the extraction For the basic bank of “consensual” knowledge about of the part of the liver, though the wave of mitosis devel- PH following liver regeneration, to our mind, it is im- ops lately (reaches a peak on the 32nd-48th hour). At the portant to study adult animals from the initiation up to same time, it is shown that if less than 30% of liver tissue termination of regeneration - in permanent, hourly - daily is removed, hepatocyte mitoses don’t develop and liver mode. Herewith, It should also be taken into considera- “regeneration” is provided by hypertrophy; As a result of tion the fact that for complete description of liver, regen- 70% of extraction, hypertrophied hepatocytes start active eration, besides study of hepatocytes’ reproduction proliferation in 24 hours after PH and liver regeneration and/or hypertrophy, the process of apoptosis should be is based on both – hypertrophy and hyperplasia36. studied as well: it should be researched, if space is The issue whether sizes of liver lobules increase or “freed” for newly produced and/or hypertrophied hepato- not still remains unresolved: it might increase due to cytes at the expense of other cells’ apoptosis? There are both - proliferation/hypertrophy of hepatocytes68 or the only a couple of works on this issue 89,90. development of new (even having unusual architectonic) It’s practically not researched how portal vein net- lobules16,69; also both processes might take place in paral- work reacts. It is the structure, which directly goes lel. In this aspect, 2 studies of the last decade deserve through portal pressure change. How other liver tubular attention52,70, which proves that on later stages of onto- structures react? How they “follow” the organ’s change in genesis as well as after PH in rats, the sizes of liver lobules volume: by “producing new branches” or increase but not their number. But to share fully these “extension/elongation” of old ones? What changes do the data is a bit difficult, since authors carried PH on imma- architectonics of microcirculatory module of liver lobes? ture rats, liver of which still keeps growing. In addition, The study in dynamics of liver’s tubular structures via in these works, it is not clearly shown whether the increase their corrosion casts (including scanning electron micros- in the number of lobules is caused by the increase in copy of corrosion micropreparations) can provide the number or size of hepatocytes. justified answer for questions, listed above. (Via this Different methods of measurement of the sizes of stud- method was studied and quite successfully, liver vascular ied structured, structures' sizes, as well as the fact that bed architectonics and particles’ microcirculatory bed, in studies are carried out on different laboratory animals with norm, cirrhosis or occlusion of the common bile duct)91–95. varied age and specific features of the liver and cell popula- The study of hepatic regeneration gives new, additional 71 tions prevent to make a clear conclusion . significance to the background of the implementation of 34 TCM&GMJ Vol. 3 Issue 1 2018 Tsomaia et al.
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