Research Institute of Medical Primatology

Sochi, Russia

Research Institute of Medical Primatology

Sochi, Russia
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News Article | May 16, 2017
Site: www.sciencemag.org

After Paolo Macchiarini’s star fell in Sweden, the Italian surgeon still had a place to shine: Russia. The Karolinska Institute (KI) in Stockholm fired him in March 2016 for multiple ethical violations, including "breach of KI’s fundamental values" and "scientific negligence." But Russia had long showered Macchiarini with funding and opportunities to perform his experimental surgeries to implant artificial tracheas, and it allowed him to stay. Now, a year later, his Russian refuge has ended as well. On 30 March, it became clear that the Russian Science Foundation (RSF) would not renew its funding for Macchiarini’s work, which now focuses on the esophagus rather than the trachea. The decision came 9 days after Nature Communications retracted a paper by Macchiarini that documented successful esophagus transplantations in rats. Minutes of a meeting made public last week show that Kazan Federal University (KFU), Macchiarini’s current employer, decided to end his research project there on 20 April, effectively firing him. “They have probably realized that it’s all based on nothing but hot air,” says Pierre Delaere of the University of Leuven in Belgium, one of the first to criticize Macchiarini’s work. Yet despite a passionate plea by four Swedish doctors who blew the whistle on Macchiarini’s work at Karolinska in 2014, Russian authorities appear to have no plans to launch a misconduct investigation of his work in Russia. Macchiarini has not said publicly what he plans to do next, and did not respond to an interview request from Science. Once considered a pioneer of regenerative surgery, Macchiarini aimed to give patients whose tracheas had been damaged a new windpipe. “Seeded” with stem cells, it was supposed to grow into a new, fully functional organ. (He initially used donor tracheas as a basis, but later switched to an artificial scaffold.) But he has been accused of painting a false picture of his patients in scientific papers, several of which have been retracted; operating without ethical approval; and lying on his CV. At least six of the eight artificial trachea recipients have died. In Sweden, where the case has plunged science into a crisis, investigations continue into allegations including involuntary manslaughter. Macchiarini’s parallel life in Russia began in February 2010, when he conducted a master class in regenerative surgery at the invitation of Mikhail Batin, president of the Science for Life Extension Foundation (SLEF), which aims to make “radical extension of life a Russian national goal,” according to its website. Eight months later, Macchiarini agreed to do a trachea transplantation, in tandem with surgeon Vladimir Parshin at the Boris Petrovsky Research National Center for Surgery in Moscow. Glowing television coverage quickly made Macchiarini a scientific star. SLEF then helped secure a $2.6 million “megagrant” from the Russian government, aimed at luring foreign talent, and additional funding from Kuban State Medical University (KSMU), a well-known medical school in Krasnodar, some 1400 kilometers south of Moscow. Macchiarini carried out four artificial trachea transplantations at Krasnodar Regional Hospital No. 1. In 2014, his work was featured in a permanent exhibition about Russia’s scientific and technological prowess at the Polytechnic Museum in Moscow. But dramatic footage of one Russian patient eventually triggered Macchiarini’s downfall in Sweden. Experimenten, a three-part documentary broadcast in January 2016, claimed that the patient, Yulia Tuulik, didn’t have a life-threatening condition; her trachea had been damaged in a car accident, but she was able to breathe through a stoma. Macchiarini and his colleagues presented Tuulik’s operation as a medical triumph at a press conference. But her trachea later collapsed, and she received a replacement, which didn’t work well either; she died in 2014. Two other Krasnodar patients have died as well; the only survivor had his transplant removed. After Experimenten aired in Sweden and a few publications about Macchiarini appeared in the Russian press, an audit by the Federal Service for Supervision of Healthcare of the Krasnodar hospital revealed that he had operated without a Russian medical license and had filed no documentation about the materials in the artificial windpipe with the state register. The hospital was ordered to correct those violations, but no sanctions were imposed. Macchiarini’s defenders have interpreted the criticism as an attack on Russia; a January article on a portal for Russian doctors, for instance, suggested that Macchiarini had come under fire in Sweden because of the success of the laboratory he founded in Krasnodar. “I’m … outraged not so much by criticism of myself, as by criticism of the conditions and standards of research in Russia,” Macchiarini himself told the website Lenta.ru. Even before Macchiarini’s megagrant ended, RSF provided him with a new grant for some $1 million annually to develop a tissue-engineered esophagus and test it in nonhuman primates. In 2016, Macchiarini asked RSF to transfer the grant from KSMU to KFU, 800 kilometers east of Moscow in Tatarstan. Since then he has worked out of the limelight. But KFU soon grew uneasy. In a December 2016 newspaper interview, KFU Rector Ilshat Gafurov said that Macchiarini would not carry out operations at KFU as long as he did not have the required papers, and would not even see patients. According to RSF’s website, Macchiarini has given 10 baboons small pieces of artificial esophagus at the Research Institute of Medical Primatology in Sochi, a city on the Black Sea; all supposedly recovered. Data from the experiment have not been published, but KFU “can guarantee that the results, whatever they may be, will reflect the real state of affairs, will be truthful,” a spokesperson for the university says. Last December, the four original whistle-blowers in Sweden sent several Russian government agencies a 57-page petition asking for a criminal investigation of Macchiarini because he “systematically falsified, omitted or glorified” data from his operations in Sweden to obtain an ethical approval for his work in Krasnodar. None of the agencies has responded, says one of the authors, Matthias Corbascio of Karolinska University Hospital. Corbascio welcomes Macchiarini’s dismissal but says it should only be the beginning: “We hope that a police investigation is initiated in Russia and that Macchiarini will face criminal charges.” (A spokesperson for the Russian health ministry says it has never received the document.) Macchiarini’s Russian patients or their relatives could sue the Krasnodar hospital, says Alexander Saversky, president of the Russian League for the Protection of Patients, if there is strong suspicion that the operations did more harm than good. So far, nobody has done that. There’s no point, Natalia Tuulik, Yulia’s mother, told a newspaper: “The court will not return my daughter to me.”


Korzaia L.I.,Research Institute of Medical Primatology | Keburia V.V.,Research Institute of Medical Primatology | Dogadov D.I.,Research Institute of Medical Primatology | Lapin B.A.,Research Institute of Medical Primatology | And 2 more authors.
Voprosy Virusologii | Year: 2016

Serum from humans (n = 646) and monkeys (n = 1867) collected during the period 1999-2013 was tested by enzyme immunoassay. Anti-HEV IgG was detected significantly more frequently (P > 0.001) in rhesus macaques (Macaca mulatta) - 45.1 ± 1.6% (n = 1001) than in cynomolgus macaques (M. fascicularis) 16.2 ± 1.8% (n = 426). Single seropositive individuals were found among M. nemestrina - 4.0±2.8% (n = 50). Anti-HEV was not detected in the sera of green monkeys (Chlorocebus aethiops) -n = 162, Papio hamadryas (n = 124), and Papio anubis - n = 104. The presence of the anti-HEV IgM indicating the cases of fresh infection in Macaca mulatta - 2.1 ± 0.5% (n = 717) and M. fascicularis - 3.5 ± 1.3% (n = 266) is of great significance. The overall frequency of detection of the anti-HEV IgG among the staff of the Adler Primate Center - 6.8 ± 2.3% (n = 118) was significantly lower (P £ 0.001) than among the population of the Greater Sochi - 15.9% ± 1.6 (n = 528). It is important that only in patients of medical institutions (clinic, hospital, cancer center), anti-HEV IgM were detected (2.7-11.8%) along with anti-HEV IgG (15-23.5%), thereby indicating the presence of acute cases of HEV infection among this population. HEV RNA was not detected in the serum of anti-HEV IgM-positive people and monkeys. Seroepidemiological data do not confirm the assumption on the ability of seropositive monkeys of Macaca genus to be a natural reservoir of HEV infection for humans.


Goncharova N.D.,Research Institute of Medical Primatology | Oganyan T.E.,Research Institute of Medical Primatology
General and Comparative Endocrinology | Year: 2017

Aging is characterized by disturbances in the functioning of the hypothalamic-pituitary-adrenal (HPA) axis, associated with disturbances in the adaptation processes and increase of the probability of the onset of post-stress syndrome. However, the individual features of age-related disorders stress reactivity of HPA axis have not been studied. The purpose was to study individual characteristics of the HPA axis responsiveness to acute psycho-emotional stress exposure (restraint, ASE) at different age periods on the model of the young adult and old physically healthy female rhesus monkeys that differ in their behavioral responses to stress, i.e., with depression-like and anxiety-like behavior (DAB) on the one hand and healthy standard (control) adaptive behavior (SB) on the other hand. No significant intergroup differences were observed in HPA axis responses to ASE in young animals. During aging the monkeys with SB showed reduced ACTH response to the ASE, whereas the monkeys with DAB demonstrated its increase. The old animals with DAB in response to ASE demonstrated the most pronounced HPA axis disorders, such as the highest levels of corticotrophin (ACTH), the lowest levels of dehydroepiandrosterone sulfate (DHEAS), reduced cortisol (F) levels and the highest values of the F/DHEAS molar ratio. The ratio F/DHEAS positively correlates with the malondialdehyde concentration in erythrocytes that is considered as the biomarker of oxidative stress. Thus, these data allow us to consider the old monkeys with DAB as individuals with higher vulnerability to the adverse effects of ASE. In addition, depression-like and anxiety-like behavior of aged primates under mild/moderate stress along with reduced DHEAS plasma concentration and increased values of F/DHEAS ratio can be used to identify individuals with increased vulnerability to ASE and accelerated aging. © 2017 Elsevier Inc.


Goncharova N.D.,Research Institute of Medical Primatology | Chigarova O.A.,Research Institute of Medical Primatology | Oganyan T.E.,Research Institute of Medical Primatology
Bulletin of Experimental Biology and Medicine | Year: 2017

Individual features of the response of the hypothalamic—pituitary—adrenal axis (HPAA) to repeated moderate stress exposure (daily 2-h restraint stress for 10 days) was studied in young female rhesus monkeys with healthy normal behavior and combined group of female rhesus monkeys with abnormal depression-like and anxious behavior. No between-group differences in the response of ACTH and cortisol were found on day 1. On day 10, a rapid and less pronounced increase in ACTH secretion was observed in all animals in comparison with day 1. Analysis of between-group differences in HPAA response showed higher increase in ACTH level and lower increase in cortisol concentration in animals with depression-like and anxious behavior. These changes were similar to the previously described differences in the response of the adenohypophysis and adrenal cortex to acute restraint stress in old monkeys with similar behavior. Thus, individuals with depression-like and anxious behavior demonstrate impaired stress-induced reactivity of HPAA as early as in young age. © 2017 Springer Science+Business Media, LLC


Meishvili N.V.,Research Institute of Medical Primatology | Chalyan V.G.,Research Institute of Medical Primatology | Lipina Y.Y.,Research Institute of Medical Primatology | Pachuliya I.G.,Research Institute of Medical Primatology
Neuroscience and Behavioral Physiology | Year: 2017

Individual variability in measures of aggressivity and anxiety in male Rhesus macaques (Macaca mulatta) was studied. The observations addressed 69 males reared in family groups and kept during the study in individual cages and then in outdoor corrals in groups consisting only of males. Measures of observer-directed aggression and anxiety noted in individual conditions were found not to be reliable predictors of measures of aggressivity and anxiety in social group conditions. Categories of males were identified with different reactions to the change in conditions. Transfer of males from individual conditions to corrals had therapeutic effects on their mental status. In corral conditions, pathological forms of self-directed behavior disappeared from the repertoires of most males. Thus, these observations show that keeping conditions can have powerful influences on the behavioral phenotype of adult male Rhesus macaques, which has to be considered when performing studies requiring analysis of aggressivity and anxiety in monkeys. © 2017 Springer Science+Business Media, LLC


Sotnichenko A.S.,Laboratory of fundamental research | Gubareva E.A.,Laboratory of fundamental research | Kuevda E.V.,Laboratory of fundamental research | Gumenyuk I.S.,Laboratory of fundamental research | And 2 more authors.
Medical News of North Caucasus | Year: 2016

Decellularization is used in biomedical engineering to isolate the extracellular matrix (ECM) from its inhabiting cells, preserving the ECM of the scaffold, which could be used for biological non-immunogenic and non- Toxic scaffolds obtainment for creation of full-fledged organs and tissues. Taking into account the importance of transferring results into clinic, the model of the non-human primates is the most suitable model for carrying out preclinical research. We have developed two protocols of Macaca mulatta esophagus decellularization by the modified detergent and enzymatic method differing in samples storage conditions, preparation for decellularization process, and also composition and duration of decellularizing agents' exposure. The obtained scaffolds maintain anatomical and morphological properties of a native esophagus as well as components of an ECM. The DNA-quantity substantially decreases when using detergents and enzymes. At the same time it is shown that organs' freezing at 30 °C requires protocol modification for lengthening of transportation and storage time and the subsequent thawing for decellularization. © Group of authors, 2016.


PubMed | Research Institute of Medical Primatology, Kuban State Medical University and RAS Research Center Kurchatov Institute
Type: Journal Article | Journal: Doklady. Biochemistry and biophysics | Year: 2016

The effect of decellularization on the biomechanical properties of macaque lungs was studied. The quality of the biological scaffold was additionally assessed by morphological methods, and the contents of extracellular matrix (ECM) fibers were determined both qualitatively and quantitatively. Histological analysis revealed no damage of structural integrity of ECM components, but the scaffold elasticity significantly decreased, which was confirmed by the changes in the hysteresis loop without a concomitant decrease in peak loads, with the mechanical strength of the samples being retained. These changes require taking additional measures to prevent a decrease in the effective lung volume.


Lapin B.A.,Research Institute of Medical Primatology | Yakovleva L.A.,Research Institute of Medical Primatology | Dzhikidze E.K.,Research Institute of Medical Primatology | Gvozdik T.E.,Research Institute of Medical Primatology | And 3 more authors.
Journal of Medical Primatology | Year: 2015

Background: In spring 2009 in Adler colony of the Institute of Medical Primatology, a large enzootic outbreak of acute intestine infection associated with pathogenic E. coli occurred and caused 5% mortality of population (209 animals). Methods: The epidemiological analysis, bacteriological investigation, postmortem examination, histological analysis, and PCR were used to identify the infectious agent. Results: Marked hemorrhagic diathesis, lethargy, dehydration, diarrhea with blood, wasting, and sometimes dystrophic changes in articular cartilages were noted. Morphologically, hemorrhagic enterocolitis and massive hemorrhages were found. PCR investigation of bacteriologically isolated E. coli characterized it as enteropathogenic and enteroinvasive E. coli. Conclusions: The outbreak in Adler colony slightly differed from similar outbreak in Florida in 2014 by more marked hemorrhagic diathesis and articular changes in some monkeys caused by polyavitaminosis developed in the course of infection. Sensitive to infection were M. mulatta, M. fascicularis, Cercopithecus aethiops, P. hamadryas and anubis, and Cebus capucinus. © 2015 John Wiley & Sons A/S.


PubMed | Research Institute of Medical Primatology
Type: Journal Article | Journal: Journal of medical primatology | Year: 2016

In spring 2009 in Adler colony of the Institute of Medical Primatology, a large enzootic outbreak of acute intestine infection associated with pathogenic E. coli occurred and caused 5% mortality of population (209 animals).The epidemiological analysis, bacteriological investigation, postmortem examination, histological analysis, and PCR were used to identify the infectious agent.Marked hemorrhagic diathesis, lethargy, dehydration, diarrhea with blood, wasting, and sometimes dystrophic changes in articular cartilages were noted. Morphologically, hemorrhagic enterocolitis and massive hemorrhages were found. PCR investigation of bacteriologically isolated E. coli characterized it as enteropathogenic and enteroinvasive E. coli.The outbreak in Adler colony slightly differed from similar outbreak in Florida in 2014 by more marked hemorrhagic diathesis and articular changes in some monkeys caused by polyavitaminosis developed in the course of infection. Sensitive to infection were M. mulatta, M. fascicularis, Cercopithecus aethiops, P. hamadryas and anubis, and Cebus capucinus.


PubMed | Research Institute of Medical Primatology
Type: Journal Article | Journal: Bulletin of experimental biology and medicine | Year: 2016

Culture of mesenchymal stem cells isolated from the bone marrow of primates by their characteristics met the requirements of stem cells. It was shown that transplantation of allogeneic mesenchymal stem cells (2 million cells per 1 kg body weight) immediately after ligation of the left anterior descending coronary artery between the middle and upper thirds led to neovascularization and capillarization of the ischemic myocardium.

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