Publications by authors named "George B Stefano"

192 Publications

Historical Insight into Infections and Disorders Associated with Neurological and Psychiatric Sequelae Similar to Long COVID.

Authors:
George B Stefano

Med Sci Monit 2021 Feb 26;27:e931447. Epub 2021 Feb 26.

Center for Cognitive and Molecular Neuroscience, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.

Long-term sequelae of coronavirus disease 2019 (COVID-19) due to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are now recognized. However, there is still a lack of consensus regarding the terminology for this emerging chronic clinical syndrome, which includes long COVID, chronic COVID syndrome, post-COVID-19 syndrome, post-acute COVID-19, and long-hauler COVID-19. In this review, I will use the term "long COVID". A review of the medical history and epidemiology of past pandemics and epidemics in modern literature review identifies common long-term post-infectious disorders, with the common finding of altered cognition. In the brain, the cerebral hypoxia induced by SARS-CoV-2 infection may be caused by mitochondrial dysfunction, resulting in "brain fog". Historically, the common symptom of altered cognition has been reported during earlier pandemics, which include the influenza pandemics of 1889 and 1892 (Russian flu), the Spanish flu pandemic (1918-1919), encephalitis lethargica, diphtheria, and myalgic encephalomyelitis (chronic fatigue syndrome or post-viral fatigue syndrome). There are similarities between chronic fatigue syndrome and the "brain fog" described in long COVID. During past viral epidemics and pandemics, a commonality of neural targets may have increased viral survival by conformational matching. The neurological and psychiatric sequelae of SARS-CoV-2 infection, or long COVID, may have emerged from neural effects that have emerged from an invertebrate and vertebrate virosphere. This review aims to present a historical overview of infections and disorders associated with neurological and psychiatric sequelae that have shown similarities with long COVID.
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http://dx.doi.org/10.12659/MSM.931447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924007PMC
February 2021

Selective Neuronal Mitochondrial Targeting in SARS-CoV-2 Infection Affects Cognitive Processes to Induce 'Brain Fog' and Results in Behavioral Changes that Favor Viral Survival.

Med Sci Monit 2021 Jan 25;27:e930886. Epub 2021 Jan 25.

Center for Cognitive and Molecular Neuroscience, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.

Alterations in brain functioning, especially in regions associated with cognition, can result from infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and are predicted to result in various psychiatric diseases. Recent studies have shown that SARS-CoV-2 infection and coronavirus disease 2019 (COVID-19) can directly or indirectly affect the central nervous system (CNS). Therefore, diseases associated with sequelae of COVID-19, or 'long COVID', also include serious long-term mental and cognitive changes, including the condition recently termed 'brain fog'. Hypoxia in the microenvironment of select brain areas may benefit the reproductive capacity of the virus. It is possible that in areas of cerebral hypoxia, neuronal cell energy metabolism may become compromised after integration of the viral genome, resulting in mitochondrial dysfunction. Because of their need for constant high metabolism, cerebral tissues require an immediate and constant supply of oxygen. In hypoxic conditions, neurons with the highest oxygen demand become dysfunctional. The resulting cognitive impairment benefits viral spread, as infected individuals exhibit behaviors that reduce protection against infection. The effects of compromised mitochondrial function may also be an evolutionary advantage for SARS-CoV-2 in terms of host interaction. A high viral load in patients with COVID-19 that involves the CNS results in the compromise of neurons with high-level energy metabolism. Therefore, we propose that selective neuronal mitochondrial targeting in SARS-CoV-2 infection affects cognitive processes to induce 'brain fog' and results in behavioral changes that favor viral propagation. Cognitive changes associated with COVID-19 will have increasing significance for patient diagnosis, prognosis, and long-term care.
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http://dx.doi.org/10.12659/MSM.930886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845145PMC
January 2021

Psychiatric Manifestations of COVID-19 and Their Social Significance.

Med Sci Monit 2020 Dec 16;26:e930340. Epub 2020 Dec 16.

Center for Cognitive and Molecular Neuroscience, First Faculty of Medicine, Charles University in Prague, Prague, NY, USA.

Alterations in complex behavioral patterns during the extended period of the COVID-19 pandemic are predicted to promote a variety of psychiatric disease symptoms due to enforced social isolation and self-quarantine. Accordingly, multifaceted mental health problems will continue to increase, thereby creating a challenge for society and the health care system in general. Recent studies show that COVID-19 can directly or indirectly influence the central nervous system, potentially causing neurological pathologies such as Alzheimer disease and Parkinson disease. Thus, chronic COVID-19-related disease processes have the potential to cause serious mental illnesses, including depression, anxiety, and sleep disorders. Importantly, mental health problems can foster systemic changes in functionally-linked neuroendocrine conditions that heighten a person's susceptibility to COVID-19 infection. These altered defense mechanisms may include compromised "self-control" and "self-care", as well as a "lack of insight" into the danger posed by the virus. These consequences may have serious social impacts on the future of COVID-19 survivors. Compounding the functionally related issues of altered mental health parameters and viral susceptibility are the potential effects of compromised immunity on the establishment of functional herd immunity. Within this context, mental health takes on added importance, particularly in terms of the need to increase support for mental health research and community-based initiatives. Thus, COVID-19 infections continue to reveal mental health targets, a process we must now be prepared to deal with.
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http://dx.doi.org/10.12659/MSM.930340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7751254PMC
December 2020

Convalescent Memory T Cell Immunity in Individuals with Mild or Asymptomatic SARS-CoV-2 Infection May Result from an Evolutionarily Adapted Immune Response to Coronavirus and the 'Common Cold'.

Med Sci Monit 2020 Nov 26;26:e929789. Epub 2020 Nov 26.

International Scientific Information, Inc., Melville, NY, USA.

Recent studies have shown a significant level of T cell immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in convalescent coronavirus disease 2019 (COVID-19) patients and unexposed healthy individuals. Also, SARS-CoV-2-reactive T memory cells occur in unexposed healthy individuals from endemic coronaviruses that cause the 'common cold.' The finding of the expression of adaptive SARS-CoV-2-reactive T memory cells in unexposed healthy individuals may be due to multiple cross-reactive viral protein targets following previous exposure to endemic human coronavirus infections. The opinion of the authors is that determination of protein sequence homologies across seemingly disparate viral protein libraries may provide epitope-matching data that link SARS-CoV-2-reactive T memory cell signatures to prior administration of cross-reacting vaccines to common viral pathogens. Exposure to SARS-CoV-2 initiates diverse cellular immune responses, including the associated 'cytokine storm'. Therefore, it is possible that the intact virus possesses a required degree of conformational matching, or stereoselectivity, to effectively target its receptor on multiple cell types. Therefore, conformational matching may be viewed as an evolving mechanism of viral infection and viral replication by an evolutionary modification of the angiotensin-converting enzyme 2 (ACE2) receptor required for SARS-CoV-2 binding and host cell entry. The authors propose that convalescent memory T cell immunity in individuals with mild or asymptomatic SARS-CoV-2 infection may result from an evolutionarily adapted immune response to coronavirus and the 'common cold'.
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http://dx.doi.org/10.12659/MSM.929789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7706138PMC
November 2020

Long-Term Respiratory and Neurological Sequelae of COVID-19.

Med Sci Monit 2020 Nov 1;26:e928996. Epub 2020 Nov 1.

International Scientific Information, Inc., Melville, NY, USA.

Since the initial reports of coronavirus disease 2019 (COVID-19) in China in late 2019, infections from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have spread rapidly, resulting in a global pandemic that has caused millions of deaths. Initially, the large number of infected people required the direction of global healthcare resources to provide supportive care for the acutely ill population in an attempt to reduce mortality. While clinical trials for safe and effective antiviral agents are ongoing, and vaccine development programs are being accelerated, long-term sequelae of SARS-CoV-2 infection have become increasingly recognized and concerning. Although the upper and lower respiratory tracts are the main sites of entry of SARS-CoV-2 into the body, resulting in COVID-19 pneumonia as the most common presentation, acute lung damage may be followed by pulmonary fibrosis and chronic impairment of lung function, with impaired quality of life. Also, increasing reports have shown that SARS-CoV-2 infection involves the central nervous system (CNS) and the peripheral nervous system (PNS) and directly or indirectly damages neurons, leading to long-term neurological sequelae. This review aims to provide an update on the mechanisms involved in the development of the long-term sequelae of SARS-CoV-2 infection in the 3 main areas of lung injury, neuronal injury, and neurodegenerative diseases, including Alzheimer disease, Parkinson disease, and multiple sclerosis, and highlights the need for patient monitoring following the acute stage of infection with SARS-CoV-2 to provide a rationale for the prevention, diagnosis, and management of these potential long-term sequelae.
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http://dx.doi.org/10.12659/MSM.928996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643287PMC
November 2020

Dysregulation of Nitric Oxide Signaling in Microglia: Multiple Points of Functional Convergence in the Complex Pathophysiology of Alzheimer Disease.

Med Sci Monit 2020 Sep 25;26:e927739. Epub 2020 Sep 25.

Department of Psychiatry, First Faculty of Medicine Charles University in Prague and General University Hospital in Prague, Center for Cognitive and Molecular Neuroscience, Prague, Czech Republic.

Current critical thinking has displaced the elaborated beta amyloid theory as the underlying unitary mechanism of Alzheimer disease (AD) in favor of concerted, long-term disruption or dysregulation of broad-based physiological processes. We present a critical discussion in which a chronic state of systemic proinflammation sustained over the course of several decades and engendered by ongoing metabolic or autoimmune disease is predicted to promote severe disruptions of central neurological processes. Specifically, long-term functional rundown of microglial-mediated phagocytic activity in concert with aberrant expression and cellular deposition of beta amyloid and tau protein facilitates formation of senile plaques and neurofibrillary tangles. Within this functional context, we hypothesize that early initiation events in the pathophysiology of AD may operationally involve a convergence of dysregulated peripheral and central constitutive nitric oxide signaling pathways resulting from a chronic state of systemic proinflammation and leading to severely dysfunctional "hyperactivated" microglia.
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http://dx.doi.org/10.12659/MSM.927739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523423PMC
September 2020

Prebiotic Formation of Protoalkaloids within Alkaline Oceanic Hydrothermal Vents in the Hadean Seafloor as a Prerequisite for Evolutionary Biodiversity.

Med Sci Monit 2020 Sep 22;26:e928415. Epub 2020 Sep 22.

Department of Psychiatry, First Faculty of Medicine Charles University in Prague and General University Hospital in Prague, Center for Cognitive and Molecular Neuroscience, Prague, Czech Republic.

The primordial origin of abiotic nitrogen fixation, which is not dependent on prokaryotes, reflects the importance of available nitrogenous compounds as an essential requirement for the emergence of life and evolutionary biodiversity. It has been hypothesized that synthesis of oxidized nitrogen in the form of nitrate (NO3-) and nitrite (NO2-), occurred in the prebiotic anoxic Hadean atmosphere. The sustained influx of atmospheric NO3- and NO2- into prebiotic Hadean oceans have been proposed to provide the essential substrates for abiotic synthesis of compounds such as ammonia (NH3) within oceanic alkaline hydrothermal vents in the seafloor. Because NH3 is an essential chemical precursor for nitrogen-containing molecular components of proteins and nucleic acids, abiotic production in high concentrations within Hadean oceanic alkaline hydrothermal vents is required for the emergence of diverse life forms. The chemical evolution of nitrogenous compounds includes the functional development of alkaloids. This commentary aims to critically discuss the possible origin of nitrogen-containing alkaloids and evolutionary processes in higher organisms, including the diverse biomedical mechanisms involved.
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http://dx.doi.org/10.12659/MSM.928415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519947PMC
September 2020

Emerging regulatory roles of opioid peptides, endogenous morphine, and opioid receptor subtypes in immunomodulatory processes: Metabolic, behavioral, and evolutionary perspectives.

Immunol Lett 2020 11 19;227:28-33. Epub 2020 Aug 19.

Department of Psychiatry, First Faculty of Medicine Charles University in Prague and General University Hospital in Prague, Center for Cognitive and Molecular Neuroscience, Prague, Czech Republic. Electronic address:

Integrated behavioral paradigms such as nociceptive processing coupled to anti-nociceptive responsiveness include systemically-mediated states of alertness, vigilance, motivation, and avoidance. Within a historical and cultural context, opium and its biologically active compounds, codeine and morphine, have been widely used as frontline anti-nociceptive agents. In eukaryotic cells, opiate alkaloids and opioid peptides were evolutionarily fashioned as regulatory factors in neuroimmune, vascular immune, and systemic immune communication and auto-immunoregulation. The significance of opioidergic regulation of immune function was validated by the identification of novel μ and δ opioid receptors on circulating leukocytes. The novel μ3 opioid receptor subtype has been characterized as an opioid peptide-insensitive and opiate alkaloid-selective G protein-coupled receptor (GPCR) that is functionally linked to the activation of constitutive nitric oxide synthase (cNOS). Opioid peptides stimulate granulocyte and immunocyte activation and chemotaxis via activation of a novel leukocyte δ2 receptor subtype. However, opiate alkaloid μ3 receptor agonists inhibit these same cellular activities. Opiate coupling to cNOS and subsequent production and release of mitochondrial nitric oxide (NO) suggests an evolutionary linkage to similar physiological events in prokaryotic cells. A subpopulation of immunocytes from Mytilus edulis and Leucophaea maderae and human granulocytes respond to low opioid concentrations, mediated by the adherence-promoting role of (D-Ala2-D-Met5)-enkephalinamide (DAMA), which is blocked by naloxone in a dose-dependent manner. Neutral endopeptidase 24.11 (NEP), or enkephalinase (CD10), is present on both human and invertebrate immunocytes. Alkaloids, including morphine, are found in both prokaryotic and eukaryotic cells and may have evolved much later in evolution through horizontal gene transfer. It is possible that opioid-mediated regulatory activities were conserved and elaborated during evolution as the central nervous system (CNS) became immunologically isolated by the blood-brain barrier. Thus, opioid receptor coupling became significant for cognitive and behavioural processes. Although opioid peptides and alkaloids work synergistically to suppress nociception, they mediate different actions in immune surveillance. Increased understanding of the evolutionary development of opioid receptors, nociceptive and anti-nociceptive pathways, and immunomodulation may help in the understanding of the development of tolerance to the clinical use of opiates for pain management. The significance of endogenous morphine's importance to evolution can be ascertained by the number of physiological tissues and systems that can be affected by this chemical messenger mechanism, which transcends pain. An integrated review is presented of opioid and opiate receptors, immunomodulation, and pain associated with inflammation, from an evolutionary perspective.
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http://dx.doi.org/10.1016/j.imlet.2020.08.007DOI Listing
November 2020

A Novel Vaccine Employing Non-Replicating Rabies Virus Expressing Chimeric SARS-CoV-2 Spike Protein Domains: Functional Inhibition of Viral/Nicotinic Acetylcholine Receptor Complexes.

Med Sci Monit 2020 May 28;26:e926016. Epub 2020 May 28.

Department of Psychiatry, First Faculty of Medicine Charles University in Prague and General University Hospital in Prague, Center for Cognitive and Molecular Neuroscience, Prague, Czech Republic.

The emergence of the novel ß-coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in a global pandemic of coronavirus disease 2019 (COVID-19). Clinical studies have documented that potentially severe neurological symptoms are associated with SARS-CoV-2 infection, thereby suggesting direct CNS penetration by the virus. Prior studies have demonstrated that the destructive neurological effects of rabies virus (RABV) infections are mediated by CNS transport of the virus tightly bound to the nicotinic acetylcholine receptor (nAChR). By comparison, it has been hypothesized that a similar mechanism exists to explain the multiple neurological effects of SARS-CoV-2 via binding to peripheral nAChRs followed by orthograde or retrograde transport into the CNS. Genetic engineering of the RABV has been employed to generate novel vaccines consisting of non-replicating RABV particles expressing chimeric capsid proteins containing human immunodeficiency virus 1 (HIV-1), Middle East respiratory syndrome (MERS-CoV), Ebolavirus, and hepatitis C virus (HCV) sequences. Accordingly, we present a critical discussion that integrates lessons learned from prior RABV research and vaccine development into a working model of a SARS-CoV-2 vaccine that selectively targets and neutralizes CNS penetration of a tightly bound viral nAChR complex.
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http://dx.doi.org/10.12659/MSM.926016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278327PMC
May 2020

Potential Immunoregulatory and Antiviral/SARS-CoV-2 Activities of Nitric Oxide.

Med Sci Monit 2020 May 26;26:e925679. Epub 2020 May 26.

Department of Psychiatry, First Faculty of Medicine Charles University in Prague and General University Hospital in Prague, Center for Cognitive and Molecular Neuroscience, Prague, Czech Republic.

Nitric oxide (NO) represents a key signaling molecule in multiple regulatory pathways underlying vascular, metabolic, immune, and neurological function across animal phyla. Our brief critical discussion is focused on the multiple roles of the NO signaling pathways in the maintenance of basal physiological states of readiness in diverse cell types mediating innate immunological functions and in the facilitation of proinflammatory-mediated adaptive immunological responses associated with viral infections. Prior studies have reinforced the critical importance of constitutive NO signaling pathways in the homeostatic maintenance of the vascular endothelium, and state-dependent changes in innate immunological responses have been associated with a functional override of NO-mediated inhibitory tone. Accordingly, convergent lines of evidence suggest that dysregulation of NO signaling pathways, as well as canonical oxidative effects of inducible NO, may provide a permissive cellular environment for viral entry and replication. In immunologically compromised individuals, functional override and chronic rundown of inhibitory NO signaling systems promote aberrant expression of unregulated proinflammatory pathways resulting in widespread metabolic insufficiencies and structural damage to autonomous cellular and organ structures. We contend that restoration of normative NO tone via combined pharmaceutical, dietary, or complex behavioral interventions may partially reverse deleterious physiological conditions brought about by viral infection linked to unregulated adaptive immune responses.
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http://dx.doi.org/10.12659/MSM.925679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7271680PMC
May 2020

An Evidence Based Perspective on mRNA-SARS-CoV-2 Vaccine Development.

Med Sci Monit 2020 May 5;26:e924700. Epub 2020 May 5.

International Scientific Information, Inc., Melville, NY, USA.

The first outbreak of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) occurred in Wuhan, Hubei Province, China, in late 2019. The subsequent COVID-19 pandemic rapidly affected the health and economy of the world. The global approach to the pandemic was to isolate populations to reduce the spread of this deadly virus while vaccines began to be developed. In March 2020, the first phase I clinical trial of a novel lipid nanoparticle (LNP)-encapsulated mRNA-based vaccine, mRNA-1273, which encodes the spike protein (S protein) of SARS-CoV-2, began in the United States (US). The production of mRNA-based vaccines is a promising recent development in the production of vaccines. However, there remain significant challenges in the development and testing of vaccines as rapidly as possible to control COVID-19, which requires international collaboration. This review aims to describe the background to the rationale for the development of mRNA-based SARS-CoV-2 vaccines and the current status of the mRNA-1273 vaccine.
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http://dx.doi.org/10.12659/MSM.924700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7218962PMC
May 2020

Emerging Roles of Blood-Borne Intact and Respiring Mitochondria as Bidirectional Mediators of Pro- and Anti-Inflammatory Processes.

Med Sci Monit 2020 Mar 30;26:e924337. Epub 2020 Mar 30.

Department of Psychiatry, First Faculty of Medicine, Center for Cognitive and Molecular Neuroscience, Charles University and General University Hospital in Prague, Prague, Czech Republic.

Over the past two decades, a major goal of our research group has been elucidation of the functional roles of several key regulatory molecules in proinflammatory preconditioning involved in the pathophysiology of seemingly diverse human disease states. By necessity, operational definitions of proinflammation must be intrinsically fluid based on recent advances in our understanding of complex regulation of innate and adaptive immune processes. Similar to systemic acute stress, a physiological proinflammatory state appears to be a key autoregulatory mechanism for maintaining optimal immune surveillance against potentially infective microorganisms, viruses, and toxic xenobiotics. Perturbation of normative biochemical and molecular mosaics of ongoing proinflammatory tone, exemplified by altered expression of pro- and anti-inflammatory cytokines and their respective protein complexes, is hypothesized to be a common modality for initiation and full expression of various autoimmune diseases and comorbid syndromes evolving from metabolic and metastatic diseases. The newly reported presence of "free" (extracellular) mitochondria exponentially adds to our hypothesis that in conditions of acute stress, a new source of potential ATP producers may be recruited and present to deal with such an acute process. Furthermore, given this phenomenon, an early surveillance role and a dysfunctional chronic inflammation-prolonging component may also be surmised.
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http://dx.doi.org/10.12659/MSM.924337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7142321PMC
March 2020

Behaviorally-Mediated Entrainment of Whole-Body Metabolic Processes: Conservation and Evolutionary Development of Mitochondrial Respiratory Complexes.

Med Sci Monit 2019 Dec 6;25:9306-9309. Epub 2019 Dec 6.

Department of Psychiatry, First Faculty of Medicine Charles University in Prague and General University Hospital in Prague, Center for Cognitive and Molecular Neuroscience, Prague, Czech Republic.

The relaxation response derives its health benefits by reestablishing "normal" equilibria between the sympathetic and parasympathetic branches of the autonomic nervous system. Recent work suggests that this behavioral training provides positive effects on mitochondrial bioenergetics, insulin secretion, and reductions in pro-inflammatory and stress-related pathways. We have previously contended, however, that correlative associations of relaxation training with positive changes in gene expression in selected biological systems are strongly suggestive of adaptive physiological changes, but do not elucidate an underlying, clinically compelling, unified mechanism of action consistent with its purported positive health effects. We surmise that any plausible model of behaviorally-mediated regulatory effects on whole-body metabolic processes must be intrinsically broad-based and multifaceted via integration of differential contributions of functionally interactive peripheral and CNS organ systems. Accordingly, the initiation of multiple cellular protective/anti-bio-senescence processes may have emerged during evolutionary development to ensure the survival of hybrid prokaryotic/eukaryotic progenitor cells, given the evolvement of oxidative metabolism and its associated negative byproducts. As an essential corollary, preservation and adaptation of multifaceted regulatory molecules, notably nitric oxide, paralleled the development of eukaryotic cell types via multifaceted stereo-selective recognition and conformational matching by complex biochemical and molecular enzyme systems. Hence, the relaxation response may be a manifestation of a metabolic corrective process/response, that may now include cognition ("awareness").
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http://dx.doi.org/10.12659/MSM.920174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6911308PMC
December 2019

Profiles of B-cell subsets in immunologically stable renal allograft recipients and end-stage renal disease patients.

Transpl Immunol 2020 02 15;58:101249. Epub 2019 Oct 15.

Transplantation Center of the 3rd Xiangya Hospital, Central South University, Changsha, Hunan 410013, People's Republic of China; Engineering & Technology Research Center for Transplantation Medicine of the National Ministry of Health, Changsha, Hunan 410013, People's Republic of China. Electronic address:

Background: Post-transplantation pharmacotherapies typically employ combinations of immunosuppressive agents that have been designed for targeted inhibition of T-cells and T-cell subsets. Studies of acute and chronic effects of clinically employed immunosuppressive agents on B-cells and B-cell subsets are significantly fewer in number and warrant further investigation. Accordingly, the goal of the present cross-sectional study is to functionally evaluate differences of B-cell subsets in patients with end-stage renal disease (ESRD) and immunologically stable renal transplant patients.

Patients And Methods: Of 103 patients who underwent renal transplantation, 73 patients were immunologically stable without rejection or infection. Among them, 34 patients were one-year post-transplantation, and 39 patients were five-year post-transplantation. The study also included 35 ESRD patients and 36 healthy volunteers. Flow cytometry identified B-cell subsets in the study groups.

Results: Renal allograft recipients had reduced percentages of total B-cells (CD19+) and regulatory B-cells (B) (CD38CD27 + CD24+) compared with healthy controls. The percentage of transitional B-cells (IgM + CD38CD24) and marginal zone (MZ) B-cells (IgD-CD27+) was reduced in transplant recipients compared with patients with ESRD and healthy volunteers. The highest percentage of plasma cells (PCs) (CD38CD27 + CD24-) was in patients with ESRD. In five-year post-transplantation group, CD38CD21- B-cells increased when compared with the other groups. Healthy volunteers and patients with ESRD had fewer unswitched memory (UM) B-cells (IgM + IgD + CD38CD27+), and increased isotype switched memory (ISM) B-cells (IgM-IgD-CD38CD27+). There was no difference in the percentage of naïve B-cells (IgD + CD27-) among diverse groups.

Conclusions: The percentages of the total, transitional, B, PCs, MZ, and UM B-cell subsets in immunologically stable renal allograft recipients were significantly different from healthy controls. However, B-cell subsets in patients with ESRD were minimally different with immunologically stable renal allograft recipients.
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http://dx.doi.org/10.1016/j.trim.2019.101249DOI Listing
February 2020

Association Between Red Blood Cell Distribution Width and Prognosis of Renal Transplant Recipients with Early-Onset Pneumonia.

Med Sci Monit 2019 Sep 4;25:6624-6630. Epub 2019 Sep 4.

Transplantation Center, Third Xiangya Hospital of Central South University, Engineering and Technology Research Center for Transplantation Medicine of National Ministry of Health, Changsha, Hunan, China (mainland).

BACKGROUND Following renal transplantation, early-onset pneumonia is a frequent and severe infection-related complication. Red blood cell distribution width (RDW) has been reported as a predictive marker among patients with infectious diseases. Therefore, the aim of this study was to explore the significance of RDW in predicting prognosis, including 60-day mortality, in renal transplant recipients with early-onset pneumonia. MATERIAL AND METHODS Clinical data from patients who developed early-onset pneumonia after renal transplantation were retrospectively reviewed. Patients were divided into 2 groups: those with an RDW ≤15.0% and those with an RDW >15.0%. The 60-day mortality, bacteremia, need for mechanical ventilation, renal transplant rejection rate, and number of admissions to the intensive care unit (ICU) were estimated by Kaplan-Meier methods. Univariate and multivariate Cox regression analyses were performed to determine the risk factors for 60-day mortality. RESULTS Among the 118 patients participating in the study, 18 (15.2%) died during the 60-day follow-up. Kaplan-Meier analysis showed a death rate of 9.38% in the group with an RDW ≤15.0%, and a death rate of 40.9% in the group with an RDW >15.0% (P<0.001). Patient prognosis, including episodes of mechanical ventilation, graft rejection, and ICU admissions were significantly different between groups (P<0.01). RDW was an independent factor related to higher 60-day mortality (HR, 1.672; 95% CI, 1.111-2.516). CONCLUSIONS Among patients with early-onset pneumonia following renal transplantation, increased RDW >15.0% was significantly associated with prognosis and 60-day mortality.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6743379PMC
September 2019

Burnout Syndrome and Lifestyle Among Primary School Teachers: A Czech Representative Study.

Med Sci Monit 2019 Jul 5;25:4974-4981. Epub 2019 Jul 5.

Department of Psychiatry, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic.

BACKGROUND Burnout is a state of vital exhaustion that is manifested on physical, cognitive, and emotional levels. Teachers work in a field where they are exposed daily to high job-related stressors, which can result in job change, a higher rate of unhappiness, and even earlier retirement. This study explored the relationship between job stressors, lifestyle, and burnout. MATERIAL AND METHODS Descriptive statistics were used to explore the burnout levels, together with t tests to compare between men and women, and regression analysis was performed to explore the relationship between the rates of burnout and lifestyle. RESULTS The overall sample size was 2394 teachers from primary schools. While males had higher emotional burnout, females reported higher physical burnout rates. We found that higher income was associated with less burnout, and a healthier lifestyle is associated with lower burnout rates. Teachers who take time for family and personal interests have significantly lower rates of burnout than those that do not. CONCLUSIONS Based on our results, we propose that teachers should be informed about the risk of burnout. We found that some teachers reported they do not know what burnout syndrome is. The primary aim should be to increase awareness. In fact, burnout is a major threat to those who are perfectionists and who tend to work overtime.
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http://dx.doi.org/10.12659/MSM.914205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6626498PMC
July 2019

Clinical Implications of the Perception of Time in Attention Deficit Hyperactivity Disorder (ADHD): A Review.

Med Sci Monit 2019 May 26;25:3918-3924. Epub 2019 May 26.

Department of Psychiatry, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic.

Attention deficit hyperactivity disorder (ADHD) is a lifelong neurodevelopmental disorder that can affect many areas of the daily life of individuals and is associated with poor health outcomes and with debilitating deficits in executive function. Recently, increasing numbers of research studies have begun to investigate the associations between neural and behavioral manifestations of ADHD. This review summarizes recent research on the perception of time in ADHD and proposes that this symptom is a possible diagnostic characteristic. Controlled studies on time perception have compared individuals with ADHD with typically developing controls (TDCs) and have used methods that include the Zimbardo Time Perspective Inventory (ZTPI). Practical approaches to time perception and its evaluation have shown that individuals with ADHD have difficulties in time estimation and discrimination activities as well as having the feeling that time is passing by without them being able to complete tasks accurately and well. Although ADHD has been associated with neurologic abnormalities in the mesolimbic and dopaminergic systems, recent studies have found that when individuals with ADHD are treated medically, their perception of time tends to normalize. The relationship between ADHD and the perception of time requires greater attention. Further studies on time perception in ADHD with other abnormalities, including executive function, might be approaches that refine the classification and diagnosis of ADHD and should include studies on its varied presentation in different age groups.
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http://dx.doi.org/10.12659/MSM.914225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6556068PMC
May 2019

Anti-Diabetogenic Properties of Mineralocorticoid Receptor Antagonists: Implications for Enhanced Safety and Efficacy of Post-Transplantation Pharmacotherapies.

Med Sci Monit 2019 Feb 10;25:1102-1104. Epub 2019 Feb 10.

Transplantation Center, Third Xiangya Hospital of Central South University, Engineering and Technology Research Center for Transplantation Medicine of National Ministry of Health, Changsha, Hunan, China (mainland).

Widespread usage of the calcineurin inhibitors tacrolimus and cyclosporine A as post-transplantation immunosuppressive agents is fraught with severe nephrotoxic and diabetogenic side effects. More recently, tapering of calcineurin inhibitor-based immunotherapies with concurrent administration of the mammalian target of rapamycin (mTOR) inhibitors sirolimus and everolimus has been employed within pharmacological regimens designed to achieve better safety and efficacy for preservation of allograft kidney function. Collected preclinical data and recent clinical study, however, indicate that usage of calcineurin inhibitors and/or mTOR blockers as immunosuppressive agents promotes equivalent diabetogenic side effects. Based on a wealth of validating preclinical studies, we contend that the favorable metabolic effects of mineralocorticoid receptor antagonists, such as spironolactone, support their inclusion in novel immunosuppressive strategies to inhibit new onset type II diabetic symptoms in post-transplantation patient populations.
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http://dx.doi.org/10.12659/MSM.914340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6378856PMC
February 2019

Augmentation of Whole-Body Metabolic Status by Mind-Body Training: Synchronous Integration of Tissue- and Organ-Specific Mitochondrial Function.

Med Sci Monit Basic Res 2019 Jan 11;25:8-14. Epub 2019 Jan 11.

Department of Psychiatry, First Faculty of Medicine Charles University in Prague and General University Hospital in Prague, Center for Cognitive and Molecular Neuroscience, Prague, Czech Republic.

The objective of our concise review is to elaborate an evidence-based integrative medicine model that incorporates functional linkages of key aspects of cortically-driven mind-body training procedures to biochemical and molecular processes driving enhanced cellular bioenergetics and whole-body metabolic advantage. This entails the adoption of a unified biological systems approach to selectively elucidate basic biochemical and molecular events responsible for achieving physiological relaxation of complex cellular structures. We provide accumulated evidence in support of the potential synergy of voluntary breathing exercises in combination with meditation and/or complementary cognitive tasks to promote medically beneficial enhancements in whole-body relaxation, anti-stress mechanisms, and restorative sleep. Accordingly, we propose that the widespread metabolic and physiological advantages emanating from a sustained series of complementary mind-body exercises will ultimately engender enhanced functional integration of cortical and limbic areas controlling voluntary respiratory processes with autonomic brainstem neural pattern generators. Finally, a unified mechanism is proposed that links behaviorally-mediated enhancements of whole-body metabolic advantage to optimization of synchronous regulation of mitochondrial oxygen utilization via recycling of nitrite and nitric oxide by iron-sulfur centers of coupled respiratory complexes and nitrite reductases.
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http://dx.doi.org/10.12659/MSMBR.913264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6505060PMC
January 2019

Chromosomal Processes in Mind-Body Medicine: Chronic Stress, Cell Aging, and Telomere Length.

Med Sci Monit Basic Res 2018 Sep 17;24:134-140. Epub 2018 Sep 17.

Department of Psychiatry, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Center for Cognitive and Molecular Neuroscience, Prague, Czech Republic.

Stress affects cellular aging and inflammatory and chromosomal processes, including telomere length, thereby potentially compromising health and facilitating disease onset and progression. Stress-related diseases and strategies to manage stress usually require integrative or behavioral therapeutic approaches that also operate on cellular levels. Mind-body medicine (MBM) uses the interaction between the mind, body, behavior, and the environment to correct physical and psychological malfunctions, thus ameliorating disease states and improving health. The relaxation response (RR) is a physiological opponent of stress and the stress response (SR) (i.e., fight-or-flight response), also invoking molecular anti-stress processes. Techniques that elicit the RR are at the core of practically all MBM interventions. We surmise that these techniques can also affect chromosomal and telomere processes, molecular aging, and the modulation of inflammatory states on cellular levels.
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http://dx.doi.org/10.12659/MSMBR.911786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6158997PMC
September 2018

The Micro-Hospital: 5G Telemedicine-Based Care.

Med Sci Monit Basic Res 2018 Jul 14;24:103-104. Epub 2018 Jul 14.

Department of Psychiatry, First Faculty of Medicine Charles University in Prague and General University Hospital in Prague, Center for Cognitive and Molecular Neuroscience, Prague, Czech Republic.

Today's medical service delivery platforms provide everything from small urgent care 'offices' to large medical centers. Since 2007, an intermediate entity for care has been established, namely, the micro-hospital. Micro-hospitals are 24-hour, small inpatient facilities with an average of 2 to 10 beds, designed to provide a diversity of healthcare services consistent with community demands. In addition, they seek to combine a cost-effective healthcare vehicle with potential time-dependent triage/transfer capabilities to a nearby large medical center. This smaller cost-effective entity represents an ideal vehicle for telemedicine, whereby specialists are always on hand for interpretation and consultation, with minimal patient waiting. In all likelihood, telemedicine, including cloud data storage and retrieval, will develop at a faster pace due to emerging 5G technology. Appropriate modification of the micro-hospital may also lead to creation of specialized centers devoted to endocrine and metabolic disorders, pulmonary diseases, and addiction medicine, which are certainly within the realm of medical necessity.
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http://dx.doi.org/10.12659/MSMBR.911436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6067046PMC
July 2018

Alkaloids, Nitric Oxide, and Nitrite Reductases: Evolutionary Coupling as Key Regulators of Cellular Bioenergetics with Special Relevance to the Human Microbiome.

Med Sci Monit 2018 May 14;24:3153-3158. Epub 2018 May 14.

Senior Advisor, International Scientific Information, Inc., Melville, NY, USA.

Typical alkaloids expressed by prokaryotic and eukaryotic cells are small heterocyclic compounds containing weakly basic nitrogen groups that are critically important for mediating essential biological activities. The prototype opiate alkaloid morphine represents a low molecular mass heterocyclic compound that has been evolutionarily fashioned from a relatively restricted role as a secreted antimicrobial phytoalexin into a broad spectrum regulatory molecule. As an essential corollary, positive evolutionary pressure has driven the development of a cognate 6-transmembrane helical (TMH) domain μ3 opiate receptor that is exclusively responsive to morphine and related opiate alkaloids. A key aspect of "morphinergic" signaling mediated by μ3 opiate receptor activation is its functional coupling with regulatory pathways utilizing constitutive nitric oxide (NO) as a signaling molecule. Importantly, tonic and phasic intra-mitochondrial NO production exerts profound inhibitory effects on the rate of electron transport, H+ pumping, and O2 consumption. Given the pluripotent role of NO as a selective, temporally-defined chemical regulator of mitochondrial respiration and cellular bioenergetics, the expansion of prokaryotic denitrification systems into mitochondrial NO/nitrite cycling complexes represents a series of evolutionary modifications of existential proportions. Presently, our short review provides selective discussion of evolutionary development of morphine, opiate alkaloids, μ3 opiate receptors, and NO systems, within the perspectives of enhanced mitochondrial function, cellular bioenergetics, and the human microbiome.
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http://dx.doi.org/10.12659/MSM.909409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5978027PMC
May 2018

Microbiome and Health: Ramifications of Intelligent Deception.

Med Sci Monit 2018 Apr 7;24:2060-2062. Epub 2018 Apr 7.

Senior Advisor, International Scientific Information, Inc., Melville, NY, USA.

Ten thousand years ago, the foundation for agricultural development and animal domestication was laid. Neolithic founder crops were carbohydrate-laden cereal grasses that facilitated transformation of hunter-gather societies into ancient civilizations with realistic capabilities for population expansion. In the last 3-4 decades, however, debilitating medical consequences of a progressively narrowed high caloric diet incorporating processed carbohydrates, animal protein, saturated fat and cholesterol, are translated into a global epidemic of obesity linked to metabolic and endocrine disorders, which, in part, emerged from the enhancement of our longevity. The initiation and progression of pathophysiological processes associated with this restrictive diet may well reside in the gastrointestinal tract. The critical role of human gut microbiome in facilitating normal gut physiology and linkages to other physiological systems points to its significance in comorbid pathologies when its diversity is compromised. Cortical desensitization to the potentially damaging effects of intentionally restricted high carbohydrate diets is progressively enhanced by compromised metabolic activities and widespread pro-inflammatory processes within all organ systems. Our cognitive ability must overcome the desire for comfort foods. The solution is simple: minimize "processed" foods and those of similar commercial origin in our diet, restoring a more diverse gut microbiome. Initially the solution may be costly, however, within the scope of sustained healthy longevity it will "payoff".
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5905352PMC
http://dx.doi.org/10.12659/msm.910248DOI Listing
April 2018

DNA MemoChip: Long-Term and High Capacity Information Storage and Select Retrieval.

Med Sci Monit 2018 Feb 26;24:1185-1187. Epub 2018 Feb 26.

Department of Psychiatry, Charles University, Center for Molecular and Cognitive Neuroscience, Prague, Czech Republic.

Over the course of history, human beings have never stopped seeking effective methods for information storage. From rocks to paper, and through the past several decades of using computer disks, USB sticks, and on to the thin silicon "chips" and "cloud" storage of today, it would seem that we have reached an era of efficiency for managing innumerable and ever-expanding data. Astonishingly, when tracing this technological path, one realizes that our ancient methods of informational storage far outlast paper (10,000 vs. 1,000 years, respectively), let alone the computer-based memory devices that only last, on average, 5 to 25 years. During this time of fast-paced information generation, it becomes increasingly difficult for current storage methods to retain such massive amounts of data, and to maintain appropriate speeds with which to retrieve it, especially when in demand by a large number of users. Others have proposed that DNA-based information storage provides a way forward for information retention as a result of its temporal stability. It is now evident that DNA represents a potentially economical and sustainable mechanism for storing information, as demonstrated by its decoding from a 700,000 year-old horse genome. The fact that the human genome is present in a cell, containing also the varied mitochondrial genome, indicates DNA's great potential for large data storage in a 'smaller' space.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841191PMC
http://dx.doi.org/10.12659/msm.908313DOI Listing
February 2018

Artificial Intelligence, DNA Mimicry, and Human Health.

Med Sci Monit 2017 Aug 14;23:3923-3924. Epub 2017 Aug 14.

Department of Psychiatry, Charles University, Center for Molecular and Cognitive Neuroscience, Prague, Czech Republic.

The molecular evolution of genomic DNA across diverse plant and animal phyla involved dynamic registrations of sequence modifications to maintain existential homeostasis to increasingly complex patterns of environmental stressors. As an essential corollary, driver effects of positive evolutionary pressure are hypothesized to effect concerted modifications of genomic DNA sequences to meet expanded platforms of regulatory controls for successful implementation of advanced physiological requirements. It is also clearly apparent that preservation of updated registries of advantageous modifications of genomic DNA sequences requires coordinate expansion of convergent cellular proofreading/error correction mechanisms that are encoded by reciprocally modified genomic DNA. Computational expansion of operationally defined DNA memory extends to coordinate modification of coding and previously under-emphasized noncoding regions that now appear to represent essential reservoirs of untapped genetic information amenable to evolutionary driven recruitment into the realm of biologically active domains. Additionally, expansion of DNA memory potential via chemical modification and activation of noncoding sequences is targeted to vertical augmentation and integration of an expanded cadre of transcriptional and epigenetic regulatory factors affecting linear coding of protein amino acid sequences within open reading frames.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5566202PMC
http://dx.doi.org/10.12659/msm.906498DOI Listing
August 2017

Biosensors: Enhancing the Natural Ability to Sense and Their Dependence on Bioinformatics.

Med Sci Monit 2017 Jun 28;23:3168-3169. Epub 2017 Jun 28.

CIDIE, National Research Council Scientific and Technical (CONICET), Catholic University of Córdoba (UCC), Córdoba, Argentina.

Single cells, as part of their evolution, acquired the ability to sense their internal and external environment, move to or away from a particular environment, the latter depending on the appropriate integration of the sensory input with motor ability. Clearly, the ability to sense stimuli must be a rapid process and one that has been selected upon for survival over long periods of time in concert with environmental challenges. Interestingly, various differing sensory inputs have their own receptors to respond to a specific stimulus.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5499630PMC
http://dx.doi.org/10.12659/msm.905800DOI Listing
June 2017

Microbiome: A Potential Component in the Origin of Mental Disorders.

Med Sci Monit 2017 Jun 21;23:3039-3043. Epub 2017 Jun 21.

Department of Psychiatry, Charles University First Faculty of Medicine and General Teaching Hospital, Center for Cognitive Molecular Neuroscience, Prague, Czech Republic.

It is not surprising to find microbiome abnormalities present in psychiatric disorders such as depressive disorders, bipolar disorders, etc. Evolutionary pressure may provide an existential advantage to the host eukaryotic cells in that it survives in an extracellular environment containing non-self cells (e.g., bacteria). This phenomenon is both positive and negative, as with other intercellular processes. In this specific case, the phenomenal amount of information gained from combined bacterial genome could enhance communication between self and non-self cells. This can be coupled to both pathological processes and healthy ones. In this review, we chose to examine potential associated disorders that may be coupled to the microbiome, from the perspective of their bidirectional communication with eukaryotic cells in the gut. Cognition, being the newest neural networking functionality to evolve, consumes a good amount of organismic energy, 30% of which arises from the gut flora. Furthermore, the mammalian gut is highly innervated and has a highly developed immune component, reflecting brain complexity. The brain-gut axis uses similar molecular messengers as the brain, which affects bacterial processes as well. Thus, any modification of normal bacterial processes may manifest itself in altered behavior/cognition, originating from the gut. The origin of some disorders associated with this bidirectional communication may be harnessed to restore normal functioning.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5489312PMC
http://dx.doi.org/10.12659/msm.905425DOI Listing
June 2017

Reciprocal Evolution of Opiate Science from Medical and Cultural Perspectives.

Med Sci Monit 2017 Jun 13;23:2890-2896. Epub 2017 Jun 13.

Department of Psychiatry, Charles University First Faculty of Medicine and General Teaching Hospital, Center for Cognitive Molecular Neuroscience, Prague, Czech Republic.

Over the course of human history, it has been common to use plants for medicinal purposes, such as for providing relief from particular maladies and self-medication. Opium represents one longstanding remedy that has been used to address a range of medical conditions, alleviating discomfort often in ways that have proven pleasurable. Opium is a combination of compounds obtained from the mature fruit of opium poppy, papaver somniferum. Morphine and its biosynthetic precursors thebaine and codeine constitute the main bioactive opiate alkaloids contained in opium. Opium usage in ancient cultures is well documented, as is its major extract morphine. The presence of endogenous opiate alkaloids and opioid peptides in animals owe their discovery to their consistent actions at particular concentrations via stereo select receptors. In vitro expression of morphine within a microbiological industrial setting underscores the role it plays as a multi-purpose pharmacological agent, as well as reinforcing why it can also lead to long-term social dependence. Furthermore, it clearly establishes a reciprocal effect of human intelligence on modifying evolutionary processes in papaver somniferum and related plant species.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5478244PMC
http://dx.doi.org/10.12659/msm.905167DOI Listing
June 2017

Aging Reversal and Healthy Longevity is in Reach: Dependence on Mitochondrial DNA Heteroplasmy as a Key Molecular Target.

Med Sci Monit 2017 Jun 5;23:2732-2735. Epub 2017 Jun 5.

, International Scientific Information, Melville, NY, USA.

Recent trends in biomedical research have highlighted the potential for effecting significant extensions in longevity with enhanced quality of life in aging human populations. Within this context, any proposed method to achieve enhanced life extension must include therapeutic approaches that draw upon essential biochemical and molecular regulatory processes found in relatively simple single cell organisms that are evolutionarily conserved within complex organ systems of higher animals. Current critical thinking has established the primacy of mitochondrial function in maintaining good health throughout plant and animal phyla. The mitochondrion represents an existentially defined endosymbiotic model of complex organelle development driven by evolutionary modification of a permanently enslaved primordial bacterium. Cellular mitochondria are biochemically and morphologically tailored to provide exponentially enhanced ATP-dependent energy production accordingly to tissue- and organ-specific physiological demands. Thus, individual variations in longevity may then be effectively sorted according to age-dependent losses of single-cell metabolic integrity functionally linked to impaired mitochondrial bioenergetics within an aggregate presentation of compromised complex organ systems. Recent empirical studies have focused on the functional role of mitochondrial heteroplasmy in the regulation of normative cellular processes and the initiation and persistence of pathophysiological states. Accordingly, elucidation of the multifaceted functional roles of mitochondrial heteroplasmy in normal aging and enhanced longevity will provide both a compelling genetic basis and potential targets for therapeutic intervention to effect meaningful life extension in human populations.
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http://dx.doi.org/10.12659/MSM.902515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5470867PMC
June 2017

Mitochondrial Heteroplasmy.

Adv Exp Med Biol 2017 ;982:577-594

International Scientific Information, Inc., 150 Broadhollow Rd, Ste 114, Melville, NY, 11747, USA.

Genetic polymorphisms, in concert with well-characterized etiology and progression of major pathologies, plays a significant role in aberrant processes afflicting human populations. Mitochondrial heteroplasmy represents a dynamically determined co-expression of inherited polymorphisms and somatic pathology in varying ratios within individual mitochondrial DNA (mtDNA) genomes with repetitive patterns of tissue specificity. The ratios of the MtDNA genomes represent a balance between healthy and pathological cellular outcomes. Mechanistically, cardiomyopathies have profound alterations of normative mitochondrial function. Certain allele imbalances in the nuclear mitochondrial genome are associated with key energy mitochondrial proteins. Mitochondrial heteroplasmy may manifest itself at critical protein expression points, e.g., cytochrome c oxidase (COX). Pathological mtDNA mutations also are associated with the development of congestive heart failure. Interestingly, mitochondrial 'normal vs. abnormal' ratios of various heteroplasmic populations may occur in families. In the translational context of human health and disease, we discuss the need for determining critical foci to probe multiple biological roles of mitochondrial heteroplasmy in cardiomyopathy.
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http://dx.doi.org/10.1007/978-3-319-55330-6_30DOI Listing
September 2017