Publications by authors named "James Giordano"

157 Publications

Ultra low doses and biological amplification: Approaching Avogadro's number.

Pharmacol Res 2021 Jun 19;170:105738. Epub 2021 Jun 19.

Professor of Neurology and Biochemistry, Georgetown University Medical Center, Washington, DC 20057, USA. Electronic address:

This paper describes evidence establishing that ultra-low doses of diverse chemical agents at concentrations from 10 to 10 M (e.g., approaching and/or less than 1 atom or molecule of a substance/cell based on Avogadro's constant - 6.022×10/mole) are capable of engaging receptor and intracellular signaling systems to elicit reproducible effects in a variety of species, from unicellular organisms to humans. Multiple experimental studies have shown that only one or very few molecules are needed to activate a cell and/or entire organism via cascade(s) of amplification mechanisms and processes. For example, ultra-low dose ligand exposure was able to activate both an individual cell, and ~3000 to 25,000 neighboring cells on average, by about 50%. Such activation of cells and whole organisms typically displayed hormetic-biphasic dose responses. These findings indicate that numerous, diverse phylogenetic systems have evolved highly sensitive detection and signaling mechanisms to enhance survival functions, such as defense against infectious agents, responses to diverse types of pheromone communications (e.g., alarm, sexual attraction), and development of several types of cellular protection/resilience processes. This suggests that ultra-low dose effects may be far more common than have been recognized to date. We posit that such findings have important implications for evolutionary theory, ecological and systems biology, and clinical medicine.
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http://dx.doi.org/10.1016/j.phrs.2021.105738DOI Listing
June 2021

Narrative view of the role of health promotion and salutogenesis in the treatment of chronic disease: viability and value for the care of cardiovascular conditions.

Cardiovasc Diagn Ther 2021 Apr;11(2):591-601

Division Health Promotion, University of Applied Sciences and Arts, Coburg, Coburg, Germany.

Health promotion provides a complementary scientific and practical approach to medicine, which may help to create, maintain and restore wellness even in the presence of disease and illness. Salutogenesis, as key concept, focuses upon the emergence of health and thus, leads to fortifying individuals' and communities' health determinants and resources. The potential integration of health promotion and medicine can contribute to a more person-centred focus of integrative care to address and realize individuals' health potential and needs, rather than merely an emphasis upon the underlying disease, such as congenital heart diseases. We posit that it is possible-and advisable-to address lifestyle modification aspects, and to change the focus of therapeutic encounters and health care programs to be more tailored to and aligned with individual needs, demands and expectations. By adopting a health promotional approach to the individual patient as person, their subjective biography, narrative and lifeworld can serve as resources for developing more beneficial coping styles, resilience and trajectories for personal growth over the life span, despite the occurrence and durability of chronic conditions, such as long-term cardiovascular disease. Implications, important contingencies and requirements for education and training of health-care professionals are addressed, as they are key issues that may affect the successful development and engagement of health promotion programs within health care systems at-large.
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http://dx.doi.org/10.21037/cdt-20-610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102269PMC
April 2021

Proceedings of the Eighth Annual Deep Brain Stimulation Think Tank: Advances in Optogenetics, Ethical Issues Affecting DBS Research, Neuromodulatory Approaches for Depression, Adaptive Neurostimulation, and Emerging DBS Technologies.

Front Hum Neurosci 2021 19;15:644593. Epub 2021 Apr 19.

Neurologischen Klinik Universitätsklinikum Würzburg, Würzburg, Germany.

We estimate that 208,000 deep brain stimulation (DBS) devices have been implanted to address neurological and neuropsychiatric disorders worldwide. DBS Think Tank presenters pooled data and determined that DBS expanded in its scope and has been applied to multiple brain disorders in an effort to modulate neural circuitry. The DBS Think Tank was founded in 2012 providing a space where clinicians, engineers, researchers from industry and academia discuss current and emerging DBS technologies and logistical and ethical issues facing the field. The emphasis is on cutting edge research and collaboration aimed to advance the DBS field. The Eighth Annual DBS Think Tank was held virtually on September 1 and 2, 2020 (Zoom Video Communications) due to restrictions related to the COVID-19 pandemic. The meeting focused on advances in: (1) optogenetics as a tool for comprehending neurobiology of diseases and on optogenetically-inspired DBS, (2) cutting edge of emerging DBS technologies, (3) ethical issues affecting DBS research and access to care, (4) neuromodulatory approaches for depression, (5) advancing novel hardware, software and imaging methodologies, (6) use of neurophysiological signals in adaptive neurostimulation, and (7) use of more advanced technologies to improve DBS clinical outcomes. There were 178 attendees who participated in a DBS Think Tank survey, which revealed the expansion of DBS into several indications such as obesity, post-traumatic stress disorder, addiction and Alzheimer's disease. This proceedings summarizes the advances discussed at the Eighth Annual DBS Think Tank.
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http://dx.doi.org/10.3389/fnhum.2021.644593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092047PMC
April 2021

Nrf2 activation putatively mediates clinical benefits of low-dose radiotherapy in COVID-19 pneumonia and acute respiratory distress syndrome (ARDS): Novel mechanistic considerations.

Radiother Oncol 2021 07 28;160:125-131. Epub 2021 Apr 28.

Departments of Neurology and Biochemistry, Georgetown University Medical Center, Washington, DC, USA. Electronic address:

Novel mechanistic insights are discussed herein that link a single, nontoxic, low-dose radiotherapy (LDRT) treatment (0.5-1.0 Gy) to (1) beneficial subcellular effects mediated by the activation of nuclear factor erythroid 2-related transcription factor (Nrf2) and to (2) favorable clinical outcomes for COVID-19 pneumonia patients displaying symptoms of acute respiratory distress syndrome (ARDS). We posit that the favorable clinical outcomes following LDRT result from potent Nrf2-mediated antioxidant responses that rebalance the oxidatively skewed redox states of immunological cells, driving them toward anti-inflammatory phenotypes. Activation of Nrf2 by ionizing radiation is highly dose dependent and conforms to the features of a biphasic (hormetic) dose-response. At the cellular and subcellular levels, hormetic doses of <1.0 Gy induce polarization shifts in the predominant population of lung macrophages, from an M1 pro-inflammatory to an M2 anti-inflammatory phenotype. Together, the Nrf2-mediated antioxidant responses and the subsequent shifts to anti-inflammatory phenotypes have the capacity to suppress cytokine storms, resolve inflammation, promote tissue repair, and prevent COVID-19-related mortality. Given these mechanistic considerations-and the historical clinical success of LDRT early in the 20th century-we opine that LDRT should be regarded as safe and effective for use at almost any stage of COVID-19 infection. In theory, however, optimal life-saving potential is thought to occur when LDRT is applied prior to the cytokine storms and before the patients are placed on mechanical oxygen ventilators. The administration of LDRT either as an intervention of last resort or too early in the disease progression may be far less effective in saving the lives of ARDS patients.
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http://dx.doi.org/10.1016/j.radonc.2021.04.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080499PMC
July 2021

Demonstrated hormetic mechanisms putatively subserve riluzole-induced effects in neuroprotection against amyotrophic lateral sclerosis (ALS): Implications for research and clinical practice.

Ageing Res Rev 2021 05 8;67:101273. Epub 2021 Feb 8.

Departments of Neurology and Biochemistry, Georgetown University Medical Center, Washington, DC, 20057, USA. Electronic address:

This paper provides evidence to support that riluzole, an FDA-approved treatment for amyotrophic lateral sclerosis (ALS), like many neuroprotective agents, displays and exerts hormetic biphasic dose responses. These findings have important implications for the experimental study and clinical treatment of ALS.
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http://dx.doi.org/10.1016/j.arr.2021.101273DOI Listing
May 2021

Professional attitudes toward the use of neuromodulatory technologies in Mexico: Insight for neuroethical considerations of cultural diversity.

CNS Spectr 2020 Dec 10:1-3. Epub 2020 Dec 10.

Neuroethics Studies Program, Pellegrino Center for Clinical Bioethics, Georgetown University Medical Center, Washington, DC, USA.

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http://dx.doi.org/10.1017/S1092852920002151DOI Listing
December 2020

Putative hormetic mechanisms and effects of atypical antipsychotic agents: Implications for study design and clinical psychopharmacotherapeutics.

Chem Biol Interact 2021 Jan 23;333:109327. Epub 2020 Nov 23.

Departments of Neurology and Biochemistry, Georgetown University Medical Center, Washington, DC, 20057, USA. Electronic address:

This paper addresses a novel putative mechanism by which atypical antipsychotic agents induce clinically significant neuroprotective effects that may be viable in the treatment of schizophrenia - and perhaps other neuropsychiatric disorders. Based upon experimental studies with multiple in vitro models (i.e., PC 12 cells, NSC-34 hybrid cells, SH-SY5Y cells, the immune cell line U-937) and several rodent in vivo models, six atypical antipsychotic drugs, within direct experimental comparisons and/or preconditioning protocol studies with six different stressor/toxic agents (i.e. rotenone, hydrogen peroxide, MPP+, serum withdrawal, beta-amyloid, and corticosterone) were demonstrated to induce neuroprotective effects with consistently hormetic dose response patterns. These findings suggest that some of the reported neuroprotective effects of atypical human antipsychotic agents are likely to be mediated by hormetic mechanisms. These findings may have important implications for both experimental study design and clinical therapeutics.
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http://dx.doi.org/10.1016/j.cbi.2020.109327DOI Listing
January 2021

Reforming the Process for Deep Brain Stimulation and Neurologic Device Approval in Rare Diseases.

JAMA Neurol 2021 01;78(1):5-6

Neuroethics Studies Program, Pellegrino Center for Clinical Bioethics, Department of Neurology, Georgetown University Medical Center, Washington, DC.

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http://dx.doi.org/10.1001/jamaneurol.2020.4232DOI Listing
January 2021

Immunomodulation Through Low-Dose Radiation for Severe COVID-19: Lessons From the Past and New Developments.

Dose Response 2020 Jul-Sep;18(3):1559325820956800. Epub 2020 Sep 22.

Department of Environmental Health Sciences, University of Massachusetts, Amherst, MA, USA.

Low-dose radiation therapy (LD-RT) has historically been a successful treatment for pneumonia and is clinically established as an immunomodulating therapy for inflammatory diseases. The ongoing COVID-19 pandemic has elicited renewed scientific interest in LD-RT and multiple small clinical trials have recently corroborated the historical LD-RT findings and demonstrated preliminary efficacy and immunomodulation for the treatment of severe COVID-19 pneumonia. The present review explicates archival medical research data of LD-RT and attempts to translate this into modernized evidence, relevant for the COVID-19 crisis. Additionally, we explore the putative mechanisms of LD-RT immunomodulation, revealing specific downregulation of proinflammatory cytokines that are integral to the development of the COVID-19 cytokine storm induced hyperinflammatory state. Radiation exposure in LD-RT is minimal compared to radiotherapy dosing standards in oncology care and direct toxicity and long-term risk for secondary disease are expected to be low. The recent clinical trials investigating LD-RT for COVID-19 confirm initial treatment safety. Based on our findings we conclude that LD-RT could be an important treatment option for COVID-19 patients that are likely to progress to severity. We advocate the further use of LD-RT in carefully monitored experimental environments to validate its effectiveness, risks and mechanisms of LD-RT.
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http://dx.doi.org/10.1177/1559325820956800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7513398PMC
September 2020

Hormesis: A potential strategic approach to the treatment of neurodegenerative disease.

Int Rev Neurobiol 2020 11;155:271-301. Epub 2020 Aug 11.

Departments of Neurology & Biochemistry, Georgetown University Medical Center, Washington, DC, United States.

This review describes neuroprotective effects mediated by pre- and post-conditioning-induced processes that act via the quantitative features of the hormetic dose response. These lead to the development of acquired resilience that can protect neuronal systems from endogenous and exogenous stresses and insult. Particular attention is directed to issues of dose optimization, inter-individual variation, and potential ways to further study and employ hormetic-based preconditioning approaches in medical and public health efforts to treat and prevent neurodegenerative disease.
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http://dx.doi.org/10.1016/bs.irn.2020.03.024DOI Listing
August 2020

The Emerging Neurobioeconomy: Implications for National Security.

Health Secur 2020 Jul/Aug;18(4):267-277

Joseph DeFranco, MS, is a Graduate Fellow, Program in Biodefense, Schar School of Policy and Government, George Mason University, Arlington, VA. Maureen Rhemann, PhD, is a Visiting Scholar, O'Neill-Pellegrino Program in Brain Science, Global Law and Policy, Georgetown University, Washington, DC. James Giordano, PhD, MPhil, is Professor, Departments of Neurology and Biochemistry, and Chief, Neuroethics Studies Program, Georgetown University Medical Center, Washington, DC; and a Senior Fellow, Project in Biosecurity, Technology, and Ethics, US Naval War College, Newport, RI.

Neuroscience and neurotechnology (neuroS/T) are techniques and tools used to assess or affect the nervous system. Current and near-future developments are enabling an expanding palette of capabilities to understand and influence brain functions that can foster wellbeing and economic growth. This "neurobioeconomy" is rapidly growing, attributable in large part to the global dissemination of knowledge that fosters and contributes to scientific innovation, invention, and commercialization. As a result, several countries have initiated programs in brain research and innovation. Not all brain sciences engender security concerns, but a predominance in global biomedical, bioengineering, wellness/lifestyle, and defense markets enables considerable power. Such power can be leveraged in nonkinetic or kinetic domains, and several countries have identified neuroS/T as viable and of growing value for use in warfare, intelligence, and national security operations. In addition to the current focus on biotechnology, the United States and its allies must acknowledge the significance of brain science and its projected impact on the economy, national security, and lifestyles. In this article, we examine growth of the neuroS/T market, discuss how the neurobioeconomy poses distinct ethical and security issues for the broader bioeconomy, provide examples of such issues that arise from specific nation-state activity and technological commercialization, and propose a risk assessment and mitigation approach that can be engaged by the economic, scientific, and security communities.
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http://dx.doi.org/10.1089/hs.2020.0009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482132PMC
May 2021

Patterns of CAG repeat instability in the central nervous system and periphery in Huntington's disease and in spinocerebellar ataxia type 1.

Hum Mol Genet 2020 08;29(15):2551-2567

Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.

The expanded HTT CAG repeat causing Huntington's disease (HD) exhibits somatic expansion proposed to drive the rate of disease onset by eliciting a pathological process that ultimately claims vulnerable cells. To gain insight into somatic expansion in humans, we performed comprehensive quantitative analyses of CAG expansion in ~50 central nervous system (CNS) and peripheral postmortem tissues from seven adult-onset and one juvenile-onset HD individual. We also assessed ATXN1 CAG repeat expansion in brain regions of an individual with a neurologically and pathologically distinct repeat expansion disorder, spinocerebellar ataxia type 1 (SCA1). Our findings reveal similar profiles of tissue instability in all HD individuals, which, notably, were also apparent in the SCA1 individual. CAG expansion was observed in all tissues, but to different degrees, with multiple cortical regions and neostriatum tending to have the greatest instability in the CNS, and liver in the periphery. These patterns indicate different propensities for CAG expansion contributed by disease locus-independent trans-factors and demonstrate that expansion per se is not sufficient to cause cell type or disease-specific pathology. Rather, pathology may reflect distinct toxic processes triggered by different repeat lengths across cell types and diseases. We also find that the HTT CAG length-dependent expansion propensity of an individual is reflected in all tissues and in cerebrospinal fluid. Our data indicate that peripheral cells may be a useful source to measure CAG expansion in biomarker assays for therapeutic efforts, prompting efforts to dissect underlying mechanisms of expansion that may differ between the brain and periphery.
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http://dx.doi.org/10.1093/hmg/ddaa139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471505PMC
August 2020

Does Green Tea Induce Hormesis?

Dose Response 2020 Jul-Sep;18(3):1559325820936170. Epub 2020 Jul 15.

Department of Biomedical and Biotechnological Sciences, School of Medicine University of Catania, Catania, Italy.

Green tea, and its principal constituent (-)-epigallocatechin-3-gallate (EGCG), are commonly shown to induce biphasic concentration/dose responses in a broad range of cell types, including non-tumor cells, and tumor cell lines. The most active area of research dealt with an assessment of neural cells with application to neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease cell models, often using preconditioning experimental protocols. The general findings demonstrate EGCG-induced hormetic effects resulting in an enhanced acquired resilience within an adaptive and temporally dependent homeodynamic framework. The biphasic dose responses displayed the typical quantitative features of the hormetic dose response with respect to the amplitude and width of the stimulatory response. These findings provide further evidence for the general occurrence of hormetic dose responses with such responses being independent of the biological model, end point, inducing agent, and mechanism. The biphasic nature of these responses has important implications since it suggests optimal dose ranges for end points of public health and therapeutic applications. These findings indicate the need to assess the entire dose-response continuum in order to better define the nature of the dose response, especially in the low-dose zone where such exposures are common in human populations.
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http://dx.doi.org/10.1177/1559325820936170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7364811PMC
July 2020

The Shield and Sword of Biosecurity: Balancing the Ethics of Public Safety and Global Preparedness.

Am J Bioeth 2020 07;20(7):142-144

Georgetown University Medical Center, and US Naval War College.

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http://dx.doi.org/10.1080/15265161.2020.1779859DOI Listing
July 2020

What we may learn - and need - from pandemic fiction.

Philos Ethics Humanit Med 2020 07 21;15(1). Epub 2020 Jul 21.

Departments of Neurology and Biochemistry, and Pellegrino Center for Clinical Bioethics, Georgetown University Medical Center, Washington DC, USA.

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http://dx.doi.org/10.1186/s13010-020-00089-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371836PMC
July 2020

Low dose radiation therapy as a potential life saving treatment for COVID-19-induced acute respiratory distress syndrome (ARDS).

Radiother Oncol 2020 06 8;147:212-216. Epub 2020 May 8.

Department of Environmental Health Sciences, School of Public Health and Health Sciences, University of Massachusetts, Amherst, United States.

The new coronavirus COVID-19 disease caused by SARS-CoV-2 was declared a global public health emergency by WHO on Jan 30, 2020. Despite massive efforts from various governmental, health and medical organizations, the disease continues to spread globally with increasing fatality rates. Several experimental drugs have been approved by FDA with unknown efficacy and potential adverse effects. The exponentially spreading pandemic of COVID-19 deserves prime public health attention to evaluate yet unexplored arenas of management. We opine that one of these treatment options is low dose radiation therapy for severe and most critical cases. There is evidence in literature that low dose radiation induces an anti-inflammatory phenotype that can potentially afford therapeutic benefit against COVID-19-related complications that are associated with significant morbidity and mortality. Herein, we review the effects and putative mechanisms of low dose radiation that may be viable, useful and of value in counter-acting the acute inflammatory state induced by critical stage COVID-19.
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http://dx.doi.org/10.1016/j.radonc.2020.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7206445PMC
June 2020

Proceedings of the Seventh Annual Deep Brain Stimulation Think Tank: Advances in Neurophysiology, Adaptive DBS, Virtual Reality, Neuroethics and Technology.

Front Hum Neurosci 2020 27;14:54. Epub 2020 Mar 27.

Laboratory for Neural Dynamics and Cognition, Rockefeller University, New York, NY, United States.

The Seventh Annual Deep Brain Stimulation (DBS) Think Tank held on September 8th of 2019 addressed the most current: (1) use and utility of complex neurophysiological signals for development of adaptive neurostimulation to improve clinical outcomes; (2) Advancements in recent neuromodulation techniques to treat neuropsychiatric disorders; (3) New developments in optogenetics and DBS; (4) The use of augmented Virtual reality (VR) and neuromodulation; (5) commercially available technologies; and (6) ethical issues arising in and from research and use of DBS. These advances serve as both "markers of progress" and challenges and opportunities for ongoing address, engagement, and deliberation as we move to improve the functional capabilities and translational value of DBS. It is in this light that these proceedings are presented to inform the field and initiate ongoing discourse. As consistent with the intent, and spirit of this, and prior DBS Think Tanks, the overarching goal is to continue to develop multidisciplinary collaborations to rapidly advance the field and ultimately improve patient outcomes.
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http://dx.doi.org/10.3389/fnhum.2020.00054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7134196PMC
March 2020

Recent Advances in Systems and Network Medicine: Meeting Report from the First International Conference in Systems and Network Medicine.

Syst Med (New Rochelle) 2020 26;3(1):22-35. Epub 2020 Feb 26.

Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.

The gathered together 200 global thought leaders, scientists, clinicians, academicians, industry and government experts, medical and graduate students, postdoctoral scholars and policymakers. Held at Georgetown University Conference Center in Washington D.C. on September 11-13, 2019, the event featured a day of pre-conference lectures and hands-on bioinformatic computational workshops followed by two days of deep and diverse scientific talks, panel discussions with eminent thought leaders, and scientific poster presentations. Topics ranged from: Systems and Network Medicine in Clinical Practice; the role of -omics technologies in Health Care; the role of Education and Ethics in Clinical Practice, Systems Thinking, and Rare Diseases; and the role of Artificial Intelligence in Medicine. The conference served as a unique nexus for interdisciplinary discovery and dialogue and fostered formation of new insights and possibilities for health care systems advances.
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http://dx.doi.org/10.1089/sysm.2020.0001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7099876PMC
February 2020

Hormesis and Ginkgo biloba (GB): Numerous biological effects of GB are mediated via hormesis.

Ageing Res Rev 2020 12 10;64:101019. Epub 2020 Jan 10.

Departments of Neurology and Biochemistry, Georgetown University Medical Center, 4000 Reservoir Road, Washington DC, USA. Electronic address:

Ginkgo biloba (GB) extracts have been shown to commonly induce biphasic dose responses in a range of cell types and endpoints (e.g., cochlea neural stem cells, cell viability, cell proliferation). The magnitude and width of the low dose stimulation of these biphasic dose responses are similar to those reported for hormetic dose responses. These hormetic dose responses occur within direct stimulatory responses as well as in preconditioning experimental protocols, displaying acquired resistance within an adaptive homeodynamic and temporal framework and repeated measurement protocols. The demonstrated GB dose responses further reflect the general occurrence of hormetic dose responses that consistently appear to be independent of the biological model, endpoint, inducing agent, and/or mechanism. These findings have important implications for consideration(s) of study designs involving dose selection, dose spacing, sample size, and statistical power. This illustrates and strengthens the need to characterize the low dose stimulatory response range and optimal dose in order to explore potential public health and clinical applications of plant-derived agents, such as GB.
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http://dx.doi.org/10.1016/j.arr.2020.101019DOI Listing
December 2020

Hypodopaminergia and "Precision Behavioral Management" (PBM): It is a Generational Family Affair.

Curr Pharm Biotechnol 2020 ;21(6):528-541

Department of Precision Addiction Management, Geneus Health, LLC., San Antonio, TX, United States.

Background/aims: This case series presents the novel Genetic Addiction Risk Score (GARS®) coupled with a customized pro-dopamine regulator matched to polymorphic reward genes having a hypodopaminergic risk.

Methods: The proband is a female with a history of drug abuse and alcoholism. She experienced a car accident under the influence and voluntarily entered treatment. Following an assessment, she was genotyped using the GARS, and started a neuronutrient with a KB220 base indicated by the identified polymorphisms. She began taking it in April 2018 and continues.

Results: She had success in recovery from Substance Use Disorder (SUD) and improvement in socialization, family, economic status, well-being, and attenuation of Major Depression. She tested negative over the first two months in treatment and a recent screening. After approximately two months, her parents also decided to take the GARS and started taking the recommended variants. The proband's father (a binge drinker) and mother (no SUD) both showed improvement in various behavioral issues. Finally, the proband's biological children were also GARS tested, showing a high risk for SUD.

Conclusion: This three-generation case series represents an example of the impact of genetic information coupled with an appropriate DNA guided "Pro-Dopamine Regulator" in recovery and enhancement of life.
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http://dx.doi.org/10.2174/1389201021666191210112108DOI Listing
July 2020

Proceedings of the Sixth Deep Brain Stimulation Think Tank Modulation of Brain Networks and Application of Advanced Neuroimaging, Neurophysiology, and Optogenetics.

Front Neurosci 2019 12;13:936. Epub 2019 Sep 12.

Department of Neurology, Center for Neuroengineering and Therapeutics, University of Pennsylvania, Philadelphia, PA, United States.

The annual deep brain stimulation (DBS) Think Tank aims to create an opportunity for a multidisciplinary discussion in the field of neuromodulation to examine developments, opportunities and challenges in the field. The proceedings of the Sixth Annual Think Tank recapitulate progress in applications of neurotechnology, neurophysiology, and emerging techniques for the treatment of a range of psychiatric and neurological conditions including Parkinson's disease, essential tremor, Tourette syndrome, epilepsy, cognitive disorders, and addiction. Each section of this overview provides insight about the understanding of neuromodulation for specific disease and discusses current challenges and future directions. This year's report addresses key issues in implementing advanced neurophysiological techniques, evolving use of novel modulation techniques to deliver DBS, ans improved neuroimaging techniques. The proceedings also offer insights into the new era of brain network neuromodulation and connectomic DBS to define and target dysfunctional brain networks. The proceedings also focused on innovations in applications and understanding of adaptive DBS (closed-loop systems), the use and applications of optogenetics in the field of neurostimulation and the need to develop databases for DBS indications. Finally, updates on neuroethical, legal, social, and policy issues relevant to DBS research are discussed.
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http://dx.doi.org/10.3389/fnins.2019.00936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6751331PMC
September 2019

Cytotoxicity models of Huntington's disease and relevance of hormetic mechanisms: A critical assessment of experimental approaches and strategies.

Pharmacol Res 2019 12 12;150:104371. Epub 2019 Aug 12.

Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, USA. Electronic address:

This paper assesses in vivo cytotoxicity models of Huntington's disease (HD). Nearly 150 agents were found to be moderately to highly effective in mitigating the pathological sequelae of cytotoxic induction of HD features in multiple rodent models. Typically, rodents are treated with a prospective HD-protective agent before, during, or after the application of a chemical or transgenic process for inducing histopathological and behavioral symptoms of HD. Although transgenic and knockout rodent models (1) display relatively high construct and face validity, and (2) are ever more routinely employed to mimic genetic-to-phenotypic expression of HD features, toxicant models are also often employed, and have served as valuable test beds for the elucidation of biochemical processes and discovery of therapeutic targets in HD. Literature searches of the toxicant HD rodent models yielded nearly 150 agents that were moderately to highly effective in mitigating pathological sequelae in multiple mouse and rat HD models. Experimental models, study designs, and exposure protocols (e.g., pre- and post-conditioning) used in testing these agents were assessed, including dosing strategies, endpoints, and dose-response features. Hormetic-like biphasic dose responses, chemoprotective mechanisms, and the translational relevance of the preclinical studies and their therapeutic implications are critically analyzed in the present report. Notably, not one of the 150 agents that successfully delayed onset and progression of HD in the experimental models has been successfully translated to the treatment of humans in a clinical setting. Potential reasons for these translational failures are (1) the inadequacy of dose-response analyses and subsequent lack of useful dosing data; (2) effective rodent doses that are too high for safe human application; (3) key differences between the experimental models and humans in pharmacokinetic/pharmacodynamic features, ages and routes of agent administration; (4) lack of robust pharmacokinetic, mechanistic or systematic approaches to probe novel treatment strategies; and (5) inadequacies of the chemically induced HD model in rats to mimic accurately the complex genetic and developmental origin and progression of HD in humans. These deficiencies need to be urgently addressed if pharmaceutical agents for the treatment of HD are going to be successfully developed in experimental models and translated with fidelity to the clinic.
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http://dx.doi.org/10.1016/j.phrs.2019.104371DOI Listing
December 2019

Ethical Contexts for the Future of Neuroethics.

AJOB Neurosci 2019 Jul-Sep;10(3):134-136

b Georgetown University Medical Center.

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http://dx.doi.org/10.1080/21507740.2019.1632969DOI Listing
August 2019

Restoring cerebral circulation and function postmortem: A multidimensional analysis.

Brain Circ 2019 Apr-Jun;5(2):94-96. Epub 2019 Jun 27.

Departments of Neurology and Biochemistry; Neuroethics Studies Program, Georgetown University Medical Center, Washington, DC, USA.

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http://dx.doi.org/10.4103/bc.bc_10_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611189PMC
June 2019

Viewing "p" through the lens of the philosophy of medicine.

Philos Ethics Humanit Med 2019 06 11;14(1). Epub 2019 Jun 11.

Departments of Neurology and Biochemistry and Neuroethics Studies Program-Pellegrino Center for Clinical Bioethics, Georgetown University Medical Center, Washington, DC, 20057, USA.

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http://dx.doi.org/10.1186/s13010-019-0077-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6558744PMC
June 2019

Aerosolized Nanobots: Parsing Fact from Fiction for Health Security-A Dialectical View.

Health Secur 2019 Jan/Feb;17(1):77-79. Epub 2019 Feb 6.

James Giordano, PhD, is Professor, Departments of Neurology and Biochemistry, and Chief, Neuroethics Studies Program, Georgetown University Medical Center, Washington, DC, and is Donovan Group Senior Fellow, Biowarfare and Biodefense, USSOCOM 2019.

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http://dx.doi.org/10.1089/hs.2018.0087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6424153PMC
August 2019

Hormesis mediates dose-sensitive shifts in macrophage activation patterns.

Pharmacol Res 2018 11 13;137:236-249. Epub 2018 Oct 13.

Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, USA.

The activation or polarization of macrophages to pro- or anti-inflammatory states evolved as an adaptation to protect against a spectrum of biological threats. Such an adaptation engages pro-oxidative mechanisms and enables macrophages to neutralize and kill threatening organisms (e.g., viruses, bacteria, mold), limit cancerous growths, and enhance recovery and repair processes. The present study demonstrates that (1) many diverse pharmacological, chemical and physical agents can mediate a dose/concentration-dependent shift between pro- and anti-inflammatory activation states, and (2) these shifts in activation states display biphasic dose-response relationships that are characteristic of hormesis. This study also reveals that preconditioning-another form of hormesis-similarly mediates tissue protection by the polarization of macrophages, but in this case, towards an anti-inflammatory phenotype. This assessment supports the generalizability and significance of hormesis in biology, medicine, and public health and further extends it to encompass the hormetic activation of macrophages.
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http://dx.doi.org/10.1016/j.phrs.2018.10.010DOI Listing
November 2018

A patient-derived cellular model for Huntington's disease reveals phenotypes at clinically relevant CAG lengths.

Mol Biol Cell 2018 11 26;29(23):2809-2820. Epub 2018 Sep 26.

Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4L8, Canada.

The huntingtin protein participates in several cellular processes that are disrupted when the polyglutamine tract is expanded beyond a threshold of 37 CAG DNA repeats in Huntington's disease (HD). Cellular biology approaches to understand these functional disruptions in HD have primarily focused on cell lines with synthetically long CAG length alleles that clinically represent outliers in this disease and a more severe form of HD that lacks age onset. Patient-derived fibroblasts are limited to a finite number of passages before succumbing to cellular senescence. We used human telomerase reverse transcriptase (hTERT) to immortalize fibroblasts taken from individuals of varying age, sex, disease onset, and CAG repeat length, which we have termed TruHD cells. TruHD cells display classic HD phenotypes of altered morphology, size and growth rate, increased sensitivity to oxidative stress, aberrant adenosine diphosphate/adenosine triphosphate (ADP/ATP) ratios, and hypophosphorylated huntingtin protein. We additionally observed dysregulated reactive oxygen species (ROS)-dependent huntingtin localization to nuclear speckles in HD cells. We report the generation and characterization of a human, clinically relevant cellular model for investigating disease mechanisms in HD at the single-cell level, which, unlike transformed cell lines, maintains functions critical for huntingtin transcriptional regulation and genomic integrity.
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http://dx.doi.org/10.1091/mbc.E18-09-0590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6249865PMC
November 2018

Looking Ahead: The Importance of Views, Values, and Voices in Neuroethics-Now.

Authors:
James Giordano

Camb Q Healthc Ethics 2018 10;27(4):728-731

The body-to-head transplant (BHT) planned to be undertaken later this year at China's Harbin Medical University by neurosurgeons Sergio Canavero and Xiaoping Ren has attracted considerable attention and criticism. The intended operation gives rise to philosophical queries about the body-brain-mind relationship and nature of the subjective self; technical and ethical issues regarding the scientific soundness, safety, and futility of the procedure; the adequacy of prior research; and the relative merit, folly, and/or danger of forging new boundaries of what is biomedically possible. Moreover, that this procedure, which has been prohibited from being undertaken in other countries, has been sanctioned in China brings into stark relief ways that differing social and political values, philosophies, ethics, and laws can affect the scope and conduct of research. Irrespective of whether the BHT actually occurs, the debate it has generated reveals and reflects both the evermore international enterprise of brain science, and the need for neuroethical discourse to include and appreciate multicultural views, values, and voices.
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http://dx.doi.org/10.1017/S096318011800021XDOI Listing
October 2018