Papers by George B Stefano
Brain Sciences, Jan 17, 2024
PubMed, Sep 1, 1999
The phenomenon of acupuncture is both complex and dynamic. Recent information demonstrates that a... more The phenomenon of acupuncture is both complex and dynamic. Recent information demonstrates that acupuncture may exert its actions on pain and immune processes. The coupling of these two systems occurs via common signaling molecules, i.e., opioid peptides. In this regard, we surmise that opioid activation leads to the processing of opioid peptides from their precursor, proenkephalin, and the simultaneous release of antibacterial peptides contained within the precursor as well. Thus, central nervous system pain circuits may be coupled to immune enhancement. Furthermore, acupuncture needle manipulation elicited signal increases bilaterally in the region of the primary and secondary somatosensory corticies in human brain as determined by magnetic resonance imaging. The maps reveal marked signal decreases bilaterally in multiple limbic and deep gray structures including the nucleus accumbens, amygdala, hypothalamus, hippocampus, and ventral tegmental area. Taken together, we surmise a major central nervous system pathway as well as local pain and immune modulation during acupuncture.
European Psychiatry, Apr 1, 2017
Background Even though cigarette smoking is a leading cause of preventable mortality, worldwide t... more Background Even though cigarette smoking is a leading cause of preventable mortality, worldwide tobacco is consumed by approximately 22% of population. Smoking is also one of the risk factors for cardiovascular disease and it impacts our brain processing as well as being one of the recognised risk factors for Alzheimer's disease. The tobacco toxins may cause these disorders, e.g., nicotine at high levels, which are inhaled, resulting in preclinical brain changes. Researchers suggest that there are differences in brain volume between smokers and non-smokers. This review examines these differences on the brain grey matter volume (GMV). Material/methods In March/April 2015: MedLine, Embasse and PsycInfo were searched using terms: "grey matter", "voxel based", "smoking" and "cigarette". Results Studies found brain GMV decreases in smokers compared to non-smokers. Furthermore, gender specific differences were found, while thalamus and cerebellum was affected in both genders decrease in olfactory gyrus was found only in male smokers. Age group differences were also found and these may suggest preexisting abnormalities that lead to nicotine dependence in younger individuals. Only one study found positive correlation between number of pack-years and GMV. Conclusion Smoking decreases the volume of grey matter in most brain areas. This decrease may be responsible for the cognitive impairment and difficulties with emotional regulation in smokers compared with non-smokers. Disclosure of interest The authors have not supplied their declaration of competing interest.
PubMed, 1991
The modulatory effects of interleukin-1 (IL-1), an immunotransmitter, and FMRFamide, a molluscan ... more The modulatory effects of interleukin-1 (IL-1), an immunotransmitter, and FMRFamide, a molluscan neuropeptide, were studied on identified neurons of Helix pomatia L. (Mollusca, Gastropoda) by using the method of two microelectrode voltage clamp. IL-1 and FMRFamide uniformly decreased the voltage-activated inward current (ICa), while the voltage-dependent outward potassium current (Inet K) increased. IL-1 and FMRFamide were shown to use the same cellular targets as used by the low molecular weight neurotransmitters.
PubMed, 1995
The effect of interleukin-4 (IL-4) was studied on voltage-gated Ca-current of the neuron RPeD1 of... more The effect of interleukin-4 (IL-4) was studied on voltage-gated Ca-current of the neuron RPeD1 of Lymnaea stagnalis L. (Mollusca, Basommatophora), using two-microelectrode voltage-clamp method. It was found that: 1. The neuron RPeD1 possessed a high voltage-activated Ca-current characterized by -40 mV activation threshold and reaching its maximum at +5+5(-)+10 mV. The activation time constant of the current was found to be a monnexponential function of the membrane potential. Currents were almost completely inactivated within 200-300 ms. 2. IL-4 (10-200 U/ml) uniformly and reversibly increased the peak value of Ca-current in a dose- and time-dependent manner (at concentrations 75, 150 and 200 U/ml the potentiation was 5.3 +/- 1.8% (n = 3), 5.5 +/- 1. (n = 3) and 14.6 +/- 7.4% (n = 4), respectively. 3. No changes in the membrane resistance and holding current were observed during IL-4 application. 4. The time constants of activation and inactivation were not affected by IL-4. The maximal conductance as the only kinetic parameter was increased under the influence of IL-4. 5. The affect in modulation of HVA Ca-current caused by IL-4 was additive between the doses of 10-15o U/ml but saturated at concentrations > 200 U/ml. 6. IL-4 antiserum was a potent inhibitor for enhancement of Ca-current by IL-4.
Frontiers in Integrative Neuroscience, Jul 14, 2022
Background: Mind-body medicine (MBM) focuses on improving our understanding of how the interactio... more Background: Mind-body medicine (MBM) focuses on improving our understanding of how the interactions between the brain, mind, body, and behavior can be used to promote health. In this narrative review, we present the basic principles of MBM, including the introduction of a rational framework for the implementation of MBM-based interventions. We also discuss the contributions of MBM to motivation and reward systems in the brain including those that may specifically involve the mitochondria. Results: MBM can be used to promote health in patients with chronic diseases, especially conditions identified as lifestyle-related. MBM builds on salutogenesis, which is a paradigm that focuses on health (as opposed to disease) determinants and the development of individual resilience and coherence factors as a means to reduce stress, decrease the burden of disease, and improve the quality of life. This approach involves several well-known principles of self-healing and self-care. MBM interventions typically include behavioral modification techniques in conjunction with cognitive work focused on stress regulation, exercise, relaxation, meditation, and nutrition. We suggest the use of the acronym "BERN" (Behavior, Exercise, Relaxation, and Nutrition) to summarize the operational framework of this approach. Discussion: Different BERN techniques act via shared autoregulatory central nervous system (CNS) reward and motivation circuitries. These systems rely on numerous neurobiological signaling pathways with overlapping effector molecules that converge, e.g., on nitric oxide (NO) as a common effector molecule. NO is critically coupled to reward physiology, stress reduction, and self-regulation as it modulates the responses of various mitochondrial, nuclear, and chromosomal processes within brain cells. NO has also been implicated in relevant outcomes (e.g., the placebo response). Conclusions: MBM interventions typically follow the BERN model and aim to strengthen health and resilience, and reduce stress. The mechanisms of action of these processes involve the CNS reward systems and correlate with placebo and self-healing pathways.
PubMed, Apr 1, 2004
Background: Amperometric nitric oxide probes are critical in evaluating real-time nitric oxide le... more Background: Amperometric nitric oxide probes are critical in evaluating real-time nitric oxide levels. This valuable tool enables one to measure spontaneous baseline levels of nitric oxide as well as 'puffs' of the gaseous signal molecule that may last for only seconds to minutes. However, in the past, many probes suffered from a lack of sensitivity, durability and reliability, causing investigators to design numerous controls to support their data. Material/methods: Our laboratory evaluated the new ISO-NOPF100 NO probe manufactured by World Precision Instruments of Sarasota, Florida. An invertebrate in vivo heart preparation was used, which presents a high degree of difficuly in obtaining nitric oxide measurements due to space limitations, resulting in physical contact of the probe with tissues. Additionally, we used in vitro invertebrate ganglionic preparations as a comparison since this tissue releases spontaneous and low levels of NO. Results: Calibration of the new probe demonstrated high linearity and sensitivity. The detection limit for this new probe was determined to be approximately two times lower than probes previously used in our laboratory. Basal nitric oxide fluctuations in Mytilus edulis heart and excised ganglia were able to be resolved in the sub-nanomolar range. Conclusions: The ISO-NOPF100 NO probe represents a significant advancement for measuring nitric oxide in real-time.
PubMed, Jul 1, 2001
Top down central nervous system (CNS) influences on the immune system and bottom up immune system... more Top down central nervous system (CNS) influences on the immune system and bottom up immune system influences on the CNS take part in a complex feedforward and feedback loop which may be responsible for initiating events and perpetuating circumstances in the course of neuropsychiatric as well as immune system diseases. In this paper the authors examine the neuroendocrine-neuroimmune stress response system, the concept of autoimmunoregulation, and recent studies of immune and pharmacological dysregulation in neuropsychiatric and psychosomatic illnesses. The authors review the recent English language literature on these subjects. Support for the hypothesis that macrophages play an important role in neurodevelopment and in the pathophysiology of various neuropsychiatric conditions is found. The interplay between neurologic and immune systems may help to uncover the pathophysiologies of certain neuropsychiatric systems. This may provide new strategies for pharmacologic anti inflammatory treatments. The monocyte /macrophage, which crosses the blood brain barrier is an essential candidate cell in the study of psychoneuroimmunology.
PubMed, May 26, 2004
Pedal ganglia excised and maintained in culture for up to 2 h, release NO at low levels. The rang... more Pedal ganglia excised and maintained in culture for up to 2 h, release NO at low levels. The range can vary between 0 to 1.1 nM. Non-stimulated immunocytes do not significantly stimulate ganglionic NO release when incubated with pedal ganglia. However, ganglia exposed to immunocytes that had been previously activated by a 30 min incubation with interleukin 1 beta, release NO significantly above basal levels. In these experiments, 91 +/- 2.5% of the non-stimulated immunocytes exhibited form factors in the 0.72 to 0.89 range (sampled prior to ganglionic addition), whereas 62 +/- 10.3% of the interleukin 1 beta stimulated immunocytes had form factors in the 0.39 to 0.49 range, demonstrating activation. Addition of the nitric oxide synthase inhibitor, L-NAME (10(-4) M), inhibited basal ganglionic NO release as well as that initiated by exposing the ganglia to activated immunocytes. Interestingly, non activated immunocytes, following ganglionic exposure, exhibited activity levels in the 13% range, representing a non significant increase. Cells exposed to interleukin 1 beta had a 65% activity level at the beginning of the experiment, followed by a drop of activity to 19 +/- 3.2% after ganglionic exposure. Repeating this last observation in the presence of L-NAME (10(-4) M), brought the activity level of the immunocytes back to the pre-ganglionic exposure level of activity, demonstrating that ganglionic NO was involved in down regulating immunocyte activity.
Acta Biologica Hungarica, Mar 1, 1999
We studied the effects of recombinant human interleukin-10 (IL-10) on invertebrate immunocytes an... more We studied the effects of recombinant human interleukin-10 (IL-10) on invertebrate immunocytes and microglia. The present report demonstrates that the spontaneous activation of invertebrate immunocytes can be specifically inhibited by recombinant human IL-10. Induced immunocyte activation by fMLP can also be significantly diminished by IL-10. This inhibition becomes apparent over hours and causes ameboid cells to become round and nonmobile. Furthermore, Mytilus edulis pedal ganglia maintained in culture, over the course of 24 hours, emit microglia. IL-10 significantly reduces this microglial egress, an action that can be diminished by concomitant exposure of the excised ganglia to an antibody specific to IL-10 as well as IL-10. The anti-IL-10 alone is without effect. Active-ameboid microglia that egress become round and inactive following IL-10 exposure, an action prevented by anti-IL-10. Lastly, a substance immunoreactively similar to human IL-10 can be detected in pedal ganglia homogenates. Taken together, and since the immunocytes and microglia are responding to IL-10, it implies that an IL-10-like substance could be present in invertebrates. In conclusion, the study demonstrates that both invertebrate immunocytes and microglia respond to IL-10, suggesting an early evolution of this generally inhibitory cytokine.
PubMed, 1999
There has long been a popular conceptual linkage between human immunodeficiency virus (HIV) acqui... more There has long been a popular conceptual linkage between human immunodeficiency virus (HIV) acquisition and substance abuse involving "needles". Indeed, in vitro studies demonstrate that these substances promote the replication of HIV. Included in these in vitro studies is a linkage or association of tissue damage and viral load with the actions HIV envelope protein gp120 with substances of abuse. However, detailed epidemiological studies have not supported this association of substance abuse and HIV acquisition, viral load and exacerbated tissue damage. It is with this understanding that we undertake a reevaluation of the in vitro studies within the context of the microvascular immune environment. In this regard, a counter-intuitive hypothesis emerges, namely, that specific substances of abuse may afford a degree of protection from HIV infection. This new hypothesis involves the neural, immune, and vascular signaling molecule nitric oxide.
PubMed, Nov 1, 1977
Serotonin and dopamine content in the central nervous system of Mytilus edulis (Bivalvia) was ass... more Serotonin and dopamine content in the central nervous system of Mytilus edulis (Bivalvia) was assayed fluorometrically. Acclimating the animals for 2 to 4 days at a constant temperature higher than the environmental temperatures produced substantial increases in endogenous central nervous system serotonin and decreases in dopamine. p-Chlorophenylalanine and alpha-propyldopacetamide not only prevented this increase but reduced serotonin levels below those of unacclimated animals. Cycloheximide decreased the magnitude of the serotonin rise due to acclimation. Endogenous gill serotonin after acclimation also was higher. Gill filaments closest to the visceral ganglia were the first to increase. The study shows that hydroxylation of tryptophan is a temperature-sensitive step and axonal transport of tryptophan hydroxylase to the periphery accounts for terminal serotonin synthesis. A central pool of serotonin distinct from the peripheral pool was demonstrated. The study supports previous evidence of dopamine exerting a regulatory influence on serotonin metabolism in M. edulis.
Cellular and Molecular Life Sciences, Jun 1, 1980
PubMed, Nov 1, 2005
Background: The ability of animals to make morphine has been in question for the last 30 years. S... more Background: The ability of animals to make morphine has been in question for the last 30 years. Studies have demonstrated that animals do contain morphine precursors and metabolites, as well as the ability to use some morphine precursors to make morphine. Material/methods: The present study uses excised ganglia from the marine invertebrate Mytilus edulis as well as whole animals. Morphine and dopamine levels were determined by high performance liquid chromatography coupled to electrochemical detection and radioimmunoassay. Tissues and whole animals were also exposed to morphine precursors and exposed to the CYP2D6 inhibitor quinidine and the tyrosine hydroxylase inhibitor alpha-methyl-para-tyrosine (AMPT). Additionally, via RT-PCR, a cDNA fragment of the CYP2D6 enzyme in the ganglia of M. edulis was identified. Results: Pedal ganglia incubated with either tyramine or tyrosine, or whole animals receiving injections, exhibited a statistically significant concentration- and time-dependent increase in their endogenous morphine and dopamine levels (2.51 +/- 0.76 ng/g for tyrosine and 2.39 +/- 0.64 ng/g for tyramine compared to approximately 1.0 ng/g morphine wet weight). Incubation with quinidine and/or AMPT diminished ganglionic morphine and dopamine synthesis at various steps in the synthesis process. We also demonstrated that CYP2D6 mediates the tyramine to dopamine step in this process, as did tyrosine hydroxylase in the step from tyrosine to L-DOPA. Furthermore, via RT-PCR, we identified a cDNA fragment of the CYP2D6 enzyme in the ganglia, which exhibits 94% sequence identity with its human counterpart. Evidence that tyrosine and tyramine were, in part, being converted to dopamine then morphine, and that this process can be inhibited by altering either or both CYP2D6 or tyrosine hydroxylase, is also provided. Conclusions: It appears that animals have the ability to make morphine. This process also appears to be dynamic in that the inhibition of one pathway allows the other to continue with morphine synthesis. Moreover, dopamine and morphine synthesis were coupled.
Neuropsychiatric Disease and Treatment, Mar 1, 2016
Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder that often persi... more Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder that often persists in adulthood. It is defined by inattention and/or hyperactivity-impulsivity. ADHD is associated with many comorbidities, including eating disorders (EDs). In the last decade, studies have reported that ADHD is linked with binge EDs, bulimia nervosa, and anorexia nervosa. Many postulates have been proposed to explain the association: 1) impulsive behavior in ADHD patients leads to disordered eating behavior; 2) other psychologic comorbidities present in ADHD patients account for eating behavior; 3) poor eating habits and resulting nutritional deficiencies contribute to ADHD symptoms; and 4) other risk factors common to both ADHD and EDs contribute to the coincidence of both diseases. Additionally, sex differences become a significant issue in the discussion of EDs and ADHD because of the higher incidence of bulimia nervosa and anorexia nervosa in females and the ability of females to mask the symptoms of ADHD. Interestingly, both EDs and ADHD rely on a common neural substrate, namely, dopaminergic signaling. Dopaminergic signaling is critical for motor activity and emotion, the latter enabling the former into a combined motivated movement like eating. This linkage aids in explaining the many comorbidities associated with ADHD. The interconnection of ADHD and EDs is discussed from both a historical perspective and the one based on the revealing nature of its comorbidities.
PubMed, Jun 1, 2005
Love is a complex neurobiological phenomenon, relying on trust, belief, pleasure and reward activ... more Love is a complex neurobiological phenomenon, relying on trust, belief, pleasure and reward activities within the brain, i.e., limbic processes. These processes critically involve oxytocin, vasopressin, dopamine, and serotonergic signaling. Moreover, endorphin and endogenous morphinergic mechanisms, coupled to nitric oxide autoregulatory pathways, play a role. Naturally rewarding or pleasurable activities are necessary for survival and appetitive motivation, usually governing beneficial biological behaviors like eating, sex, and reproduction. Yet, a broad basis of common signaling and beneficial neurobiological features exists with connection to the love concept, thereby combining physiological aspects related to maternal, romantic or sexual love and attachment with other healthy activities or neurobiological states. Medical practice can make use of this concept, i.e., mind/body or integrative medicine. Thus, love, pleasure, and lust have a stress-reducing and health-promoting potential, since they carry the ability to heal or facilitate beneficial motivation and behavior. In addition, love and pleasure ensure the survival of individuals and their species. After all, love is a joyful and useful activity that encompasses wellness and feelings of well-being.
Medical Science Monitor, Feb 16, 2021
Long-term sequelae of coronavirus disease 2019 (COVID-19) due to infection with severe acute resp... more 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.
Journal of Immunology, Feb 1, 1995
Human peripheral blood granulocytes previously were found to contain opioid delta 2-receptors med... more Human peripheral blood granulocytes previously were found to contain opioid delta 2-receptors mediating stimulation by opioid peptides of chemotaxis. Studies presented in this work indicate that granulocytes also contain opiate alkaloid-selective, opioid peptide-insensitive receptors mediating inhibition by morphine and other opiates of cytokine-induced activation and chemotaxis. Binding studies with [3H]morphine and [3H]diprenorphine ([3H]DPN) indicated the presence of receptor sites, at considerable density with affinities and selectivity for opiates comparable with those of the mu 3-receptor of human peripheral blood monocytes (macrophages). The influence of the guanosine 5'-triphosphate (GTP) analogue GppNHp on binding indicated that the granulocyte receptor was linked to a G protein. Morphine but not opioid peptides interfered with activation and/or chemotaxis of the granulocytes induced by TNF-alpha, IL-1 alpha, IL-8, and FMLP (chemotactic peptide). These effects of morphine were blocked by the antagonist naloxone. Levorphanol inhibited TNF-alpha-induced activation, and also potentiated the inhibition by morphine. Furthermore, in binding assays, levorphanol enhanced the affinity of the receptor for morphine. Dextrorphan had no effect on activation or chemotaxis, and it also had no effect on binding, indicative of stereoselectivity for the effect of levorphanol. It is concluded that human granulocytes contain opiate alkaloid-selective mu 3-receptors that mediate inhibitory effects of morphine on cellular activation by cytokines.
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Papers by George B Stefano