This book establishes and specifies a rigorously scientific and clinically valid basis for nonpharmaceutical approaches to many common diseases and disorders found in clinical settings. It includes lifestyle and supplement recommendations for beginning and maintaining autonomic nervous system and mitochondrial health and wellness. The book is organized around a six-pronged mind-body wellness program and contains a series of clinical applications and frequently asked questions. The physiologic need and clinical benefit and synergism of all six aspects working together are detailed, including the underlying biochemistry, with exhaustive references to statistically significant and clinically relevant studies. The book covers a range of clinical disorders, including anxiety, arrhythmia, atherosclerosis, bipolar disease, dementia, depression, fatigue, fibromyalgia, heart diseases, hypertension, mast cell disorder, migraine, and PTSD. Clinical Autonomic and Mitochondrial Disorders: Diagnosis, Prevention, and Treatment for Mind-Body Wellness is an essential resource for physicians, residents, fellows, medical students, and researchers in cardiology, primary care, neurology, endocrinology, psychiatry, and integrative and functional medicine. It provides therapy options to the indications and diagnoses published in the authors' book Clinical Autonomic Dysfunction (Springer, 2014).
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Increases in TNFα have been shown to impair oligodendrocyte differentiation, promote mitochondrial dysfunction, and lead to demyelination [69]. As oligodendrocytes are mechanistically important in AD pathology [70], and are impaired by increased levels of TNFα [69], our findings provide insight into a mechanism through which glyphosate may exacerbate neurodegenerative and neuroimmune-related diseases. Specifically, as neuroinflammation has been shown to play a key role in AD initiation and in progression [71], and genome-wide association studies (GWAS) have highlighted several immune genes as risk factors for AD [72, 73]. Glyphosate exposure may lead to an earlier onset or an accelerated progression of AD pathology. Since TNFα is commonly elevated in AD [16], we anticipate glyphosate has an additive effect on pathology and works to exacerbate the neurobiological events underlying this disease. The implications of this potential link would provide causative support to the correlation between glyphosate application to corn and soy crops and the rise in deaths due to AD. While there are many correlations between glyphosate and various illnesses, our goal is to shed light on the correlation between glyphosate application and AD. Future work will focus on uncovering the molecular overlap between glyphosate exposure and AD pathology. Specifically, we will focus on determining if glyphosate exposure is capable of exacerbating amyloid pathology and inducing cell death, in vivo in mouse models of AD.
As analyses of the small mitochondrial genome gave only limited information, Pääbo now took on the enormous challenge of sequencing the Neanderthal nuclear genome. At this time, he was offered the chance to establish a Max Planck Institute in Leipzig, Germany. At the new Institute, Pääbo and his team steadily improved the methods to isolate and analyze DNA from archaic bone remains. The research team exploited new technical developments, which made sequencing of DNA highly efficient. Pääbo also engaged several critical collaborators with expertise on population genetics and advanced sequence analyses. His efforts were successful. Pääbo accomplished the seemingly impossible and could publish the first Neanderthal genome sequence in 2010. Comparative analyses demonstrated that the most recent common ancestor of Neanderthals and Homo sapiens lived around 800,000 years ago.
Krause J, Fu Q, Good JM, Viola B, Shunkov MV, Derevianko AP, Pääbo S. The complete mitochondrial DNA genome of an unknown hominin from southern Siberia. Nature. 2010:464:894-897.
An acquired intrinsic abnormality of tissue O2 extraction and cellular O2 utilization, primarily related to mitochondrial impairment, defines the concept of cytopathic hypoxia, and the resulting cellular bioenergetic failure could represent an important mechanism of organ dysfunction in sepsis [19]. Mitochondrial defects have been demonstrated in several tissues obtained from animals in various models of sepsis, and limited data also exist on altered mitochondrial metabolism in human biopsy samples or circulating blood cells [20]. The detection of cytopathic hypoxia, however, is still not feasible at the bedside, although new techniques such as the measurement of mitochondrial O2 tension using protoporphyrin IX-Triplet State Lifetime Technique (PpIX-TSLT) are currently being developed [21]. Furthermore, impaired O2 extraction in sepsis does not necessary imply cytopathic hypoxia, as it may be related to impaired microcirculation.
Theoretically, the increased anaerobic CO2 generation in conditions of cytopathic hypoxia could result in increased anaerobic VCO2 leading to an increased Pv-aCO2 gap. This assumption has been evaluated in a porcine model of high dose metformin intoxication, which induces mitochondrial defects comparable to cyanide poisoning [22]. As expected, treated pigs exhibited reduced VO2 and marked lactic acidosis, in spite of preserved systemic DO2. However, although VCO2 decreased less than VO2, suggesting some anaerobic VCO2, no significant increase in Pv-aCO2 gap was noted. In a human case report of massive metformin intoxication, Waldauf et al. also reported no elevation in Pv-aCO2 gap despite major lactic acidosis and reduced aerobic VO2, as detected by increased SvO2 [23]. Therefore, although data are very limited, cytopathic dysoxia related to impaired mitochondrial respiration appears not to widen the Pv-aCO2 gap.
The defect in oxygen extraction observed during states of sepsis and shock is not only due to alterations in microcirculatory function. In some cases, resuscitation in terms of restored macrohemodynamic and microcirculatory parameters does not lead to clinical improvement and indirect indications of tissue hypoxia, such as high serum lactate, remain. Reduced cellular oxygen consumption, i.e., caused by mitochondrial dysfunction, could mimic such states. Cellular metabolic adaptation could also lead to reduced oxygen extraction and subsequently to a reduced ability of the mitochondria to produce ATP. It is not even unthinkable that under specific circumstances an apparent microcirculatory dysfunction might be an epiphenomenon caused by an in itself adequate adaptation of the microcirculation to an adapted or failing utilization of oxygen and nutrients by parenchymal cells. In any case, mitochondrial alterations in states of shock and sepsis have long been observed (3). If reduced mitochondrial oxygen consumption, either caused by mitochondrial dysfunction due to direct damage or as part of an adaptation mechanism, exists in the presence of normal microcirculatory oxygen transport, then this would have a dramatic impact on the current understanding of resuscitation medicine. Recently, evidence that this might be the case is emerging from both animal and clinical studies. Current resuscitation is entirely focused on promoting oxygen transport to tissues via convection and passive diffusion (4).
Research on the microcirculation in critical illness has been greatly boosted by the emergence of bedside tools that allow direct visualization of the microcirculation of a patient, for example under the tongue (5,6). To further unravel the pathophysiological mechanisms and better understand the interaction between microcirculatory impairment and alterations at the cellular and mitochondrial level we need tools that allow us to look beyond the microcirculation, probing directly aspects of cellular metabolism. Ultimately, the clinician should have access to bedside tools that enable monitoring and verification of treatment success at the microcirculatory, cellular and mitochondrial level. Such tools are currently being developed and tested both in the laboratory and in clinical trials. In this review, we will briefly discuss mitochondrial function, adaptation, causes of dysfunction, the concepts of cytopathic hypoxia and loss of hemodynamic coherence. We will briefly discuss ways to look at the mitochondria in the clinical setting, with a special focus on the novel COMET device. The COMET allows, at the bedside, direct measurement of mitochondrial oxygenation and respiration by an optical technique.
Mitochondria are double-membrane organelles found in almost all cell types, with the exception of erythrocytes. One of the main functions of mitochondria is to generate adenosine triphosphate (ATP) through oxidative phosphorylation. Over the last two decades, mitochondrial research has undergone a renaissance. Apart from its role in cell bioenergetics, a whole series of discoveries revealed mitochondrial roles in cell death, disease pathology, aging, thermogenesis, oxidative stress, cell signaling and cellular regulation. A review series about the role of mitochondria in aging and various pathophysiological states has been recently published elsewhere (1). The following paragraphs will only provide a short overview of mitochondrial function.
Mitochondria are the primary consumers of oxygen and are responsible for approximately 98% of total body oxygen consumption. Oxygen is ultimately used at complex IV of the electron transport chain in the inner mitochondrial membrane. Reduced nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH2), generated in the Krebs cycle, are transferred from carrier molecules to the electron transport chain on complex I and II respectively. The resulting electron transport through the chain causes protons to be pumped to the intermembrane space. This proton pumping causes an electrochemical potential over the inner membrane that is used to convert adenosine diphosphate (ADP) to ATP by ATP synthase. ATP is the energy currency of the cells and used for driving cellular processes like maintaining membrane potentials, protein synthesis and replication. 2ff7e9595c
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