bluuebunny/crossref_metadata_2025_split huggingface dataset:
“Alternative” Ketogenic Diets
Authors: Neal Elizabeth 
Published: November 2017

AbstractAs the classical ketogenic diet fast approaches a centennial anniversary, the wider ketogenic landscape has expanded considerably both in application and implementation. Although still extensively used today, this traditional dietary therapy has been the basis for development of alternative ketogenic protocols. One ketogenic diet incorporating medium chain fatty acids is used for many children and adolescents, who benefit from the generous carbohydrate allowance facilitated by the increased ketogenic potential of medium chain triglycerides. More recently, two less restrictive dietary approaches have been developed: the low glycemic index treatment and the modified Atkins diet. These are now being used worldwide as the advantages of a more liberal ketogenic diet are recognized, especially in adults and older children, supported by an increasing body of scientific data. This chapter explores the background and evidence for use of these alternative ketogenic diets.
Ketogenic Diet for Other Epilepsies
Authors: Hsieh David T. , Thiele Elizabeth A. 
Published: November 2017

Abstract
The ketogenic diet is the treatment of choice for epilepsy in certain disorders of brain metabolism, in particular glucose transporter protein 1 deficiency and pyruvate dehydrogenase deficiency. The International Ketogenic Diet Study Group has listed several other conditions for which the ketogenic diet has been reported as being particularly beneficial and could be offered earlier. Whether efficacy in these conditions is due in part to the broad-spectrum efficacy of the ketogenic diet or to specific mechanisms specific to these conditions is still under investigation. This chapter discusses the use of dietary therapies for the treatment of epilepsy in certain genetic disorders, including Rett syndrome and tuberous sclerosis complex, as listed by the International Ketogenic Diet Study Group, and additionally discusses the use of epilepsy dietary therapies in patients with Angelman syndrome and Sturge-Weber syndrome.
Preventing Side Effects and Diet Discontinuation
Authors: Herren Cherie L. , Said Rana R. 
Published: November 2017

Abstract
Generally, the ketogenic diet is well tolerated. On average, sixty percent of patients remain on the diet for over six months; those who stop typically do so due to lack of efficacy rather than tolerability. Common side effects include constipation, vomiting, acidosis, and vitamin/mineral deficiencies. More significant side effects are rare, but include pancreatitis, hepatitis, kidney stones, and cardiomyopathy. With appropriate monitoring and supplementation, these adverse effects can be minimized so the patient can remain on the diet as long as indicated. In addition, there may be social issues, including refusal to eat and managing special occasions and holidays. With support and resources, most families are able to overcome these obstacles. Weaning from dietary therapy must be done gradually and with close supervision, as there may be an increase in seizures. Patients must be provided support and direction on how to safely discontinue the diet.
Glucose and Ketone Metabolism in the Aging Brain
Authors: Cunnane Stephen C. , Courchesne-Loyer Alexandre , St-Pierre Valerie , Vandenberghe Camille , Croteau Etienne , Castellano Christian-Alexandre 
Published: November 2017

Abstract
Brain glucose uptake is impaired in Alzheimer’s disease (AD). A key question is whether cognitive decline could be delayed if this defect were at least partly corrected or bypassed. Ketones (or ketone bodies) such as beta-hydroxybutyrate and acetoacetate are the brain’s main alternative fuels. Several studies have shown that in mild-to-moderate AD, brain ketone uptake is similar to that of healthy age-matched controls. Published clinical trials show that increasing ketone availability to the brain via nutritional ketosis has modest benefits on cognitive outcomes in mild-to-moderate AD and in mild cognitive impairment. Nutritional ketosis can be safely achieved by a high-fat ketogenic diet or supplements providing medium chain triglycerides. Given the acute dependence of the brain on its energy supply and the ineffectiveness of current therapeutic strategies for AD consideration be given to correcting the underlying problem of deteriorating brain fuel supply during aging.
Ketogenic Diet and Ketones for the Treatment of Traumatic Brain and Spinal Cord Injury
Authors: Streijger Femke , Plunet Ward T. , Tetzlaff Wolfram 
Published: November 2017

AbstractKetogenic diets (KD)—high in fat, adequate in protein, and very low in carbohydrates—were developed almost a century ago and are still used clinically for drug-resistant epilepsy and some rare metabolic disorders. Possible new indications for cancers, diabetes, obesity, and neurodegenerative disorders are being trialed in humans based on a growing body of preclinical data showing efficacy. However the underlying mechanisms of KD remain incompletely understood. This chapter focuses on the neuroprotective effects of KD after spinal cord injury (SCI) and traumatic brain injury (TBI), and discusses possible mechanisms of action. It considers the possible role of ketone bodies as alternative fuels for mitochondrial energy utilization and the actions of ketones outside the mitochondria as agonists of antioxidant and anti-inflammatory pathways. It places these into context with the known pathophysiology of SCI and TBI, and discusses possible roles of KD and ketone bodies for their treatment.
Anti-Inflammatory Effects of a Ketogenic Diet
Authors: Dupuis Nina , Auvin Stéphane 
Published: November 2017

Abstract
The high-fat, low-carbohydrate ketogenic diet (KD) is an established and proven treatment for pharmacoresistant epilepsy. Recently, the KD is being explored for some inflammation-induced epileptic encephalopathies. Given the broad neuroprotective properties of the KD in various experimental models of neurological disorders, there are yet additional potential future uses. Consistent with this, there is growing evidence that the KD exerts anti-inflammatory activity. Ketone bodies, caloric restriction, and polyunsaturated fatty acids might be involved in the modulation of inflammation by the KD. This chapter reviews the evidence that, in part through anti-inflammatory effects, the KD holds promise in the treatment of certain epileptic disorders, neuropathic pain, multiple sclerosis, and Parkinson’s disease.
Overview of Ketogenic Diet in the Laboratory
Authors: Boison Detlev 
Published: November 2017

Abstract
Increased clinical interest in the ketogenic diet and similar metabolic treatments has naturally spurred research into mechanisms underlying their anticonvulsant/antiepileptogenic efficacy; significant progress and new insights are being made after many decades of relative obscurity. This section, “Ketogenic Diet in the Laboratory,” includes discussions of a number of molecular targets that are affected by ketogenic diet feeding. New insights into mechanisms, combined with clinical observations, are potentially expanding the utilitiy of this metabolic approach. In parallel, several alternative experimental methods to either elucidate or mobilize ketogenic diet mechanisms are explored. Based on this laboratory research, putative and novel uses for metabolic treatments are proposed.
Ketogenic Diet and PPARgamma
Authors: Simeone Timothy A. 
Published: November 2017

Abstract
The ketogenic diet (KD) is an effective therapy for many patients with refractory epilepsy. It engages a wide array of antioxidant and anti-inflammatory processes and improves mitochondrial function, which is thought to underlie its neuroprotective, antiseizure, and disease-modifying effects. Potential roles of ketone bodies in these mechanisms are discussed elsewhere in this volume. This chapter focuses on the role of KD fatty acids as potential ligands for the nutritionally regulated nuclear transcription factor peroxisome proliferator activated receptor gamma (PPARgamma). PPARgamma regulates many of the pathways identified in the mechanism of the KD and, in recent years, has become a potential therapeutic target for neurodegenerative diseases. This chapter reviews what is known concerning PPARgamma in the brain, the evidence that PPARgamma has neuroprotective and antiseizure properties, and the evidence suggesting that PPARgamma may be involved in the antiseizure mechanisms of the ketogenic diet.
Metabolic Therapy and Pain
Authors: Ruskin David N. 
Published: November 2017

Abstract
Chronic pain is associated strongly with poor quality of life. Drug treatments for pain can be problematic; with the understanding that chronic pain syndromes often involve derangement of homeostasis, there is an increased interest in applying nonpharmacological metabolic therapies. This chapter surveys clinical and animal research into the effects of fasting, calorie restriction, ketogenic diet, and polyunsaturated fatty acid supplementation on pain. These dietary treatments can significantly ameliorate pain in inflammatory and neuropathic disorders. The choice among these treatments might depend on the specific pain syndrome and the tolerance of the patient for particular dietary modifications. Several possible mechanisms are discussed, some of which might be in common among these treatments, and some treatments might engage multiple mechanisms. Multiple mechanisms acting together could be ideal for restoring the disordered metabolism underlying some pain syndromes.
Ketogenic Diet, Aging, and Neurodegeneration
Authors: Xu Kui , LaManna Joseph C. , Puchowicz Michelle A. 
Published: November 2017

AbstractThe brain is normally completely dependent on glucose, but is capable of using ketones as an alternate energy source, as occurs with prolonged starvation or chronic feeding of a ketogenic diet. Research has shown that ketosis is neuroprotective against ischemic insults in rodents. This review focuses on investigating the mechanistic links to neuroprotection by ketosis in the aged. Recovery from stroke and other pathophysiological conditions in the aged is challenging. Cerebral metabolic rate for glucose, cerebral blood flow, and the defenses against oxidative stress are known to decline with age, suggesting dysfunction of the neurovascular unit. One mechanism of neuroprotection by ketosis involves succinate-induced stabilization of hypoxic inducible factor-1alpha (HIF1α) and its downstream effects on intermediary metabolism. The chapter hypothesizes that ketone bodies play a role in the restoration of energy balance (stabilization of ATP supply) and act as signaling molecules through the up-regulation of salvation pathways targeted by HIF1α.
Endocrine and Reproductive Effects of Ketogenic Diets
Authors: Harney Jacob P. , Gudsnuk Kathryn , Patel Ami , Vellipuram Anantha R. , Bandaru Sathyajit , Butler David 
Published: November 2017

Abstract
This chapter reviews endocrine, behavioral, and reproductive outcomes of the ketogenic diet (KD) in rodent mouse and rat models. KD treatment can result in conditions seen in metabolic syndrome, including dyslipidemia and inflammation. Females raised on low protein KDs will experience delayed puberty onset. Results presented suggest an increase in ketones and a decrease in spatial memory as percent protein drops. Postpubertal female pups fed KD experienced similar cognitive decline to KD-fed dams, despite consuming only normal rodent chow since weaning. This finding is consistent with the development of anatomical differences in the brains of pups from KD-fed versus rodent chow–fed controls. A thorough evaluation of the effects of different lipid and protein profiles (amount and type) will be necessary if KDs are going to be safe and effective long-term therapies for both sexes and in neurological disorders besides pediatric intractable epilepsy.
Metabolic Seizure Resistance via BAD and KATP Channels
Authors: Martínez-François Juan Ramón , Danial Nika N. , Yellen Gary 
Published: November 2017

Abstract
On a ketogenic diet, ketone bodies provide an alternative fuel, replacing much of the glucose used ordinarily by the brain. This switch is thought to underlie its anticonvulsant effects. Brain fuel utilization can also be modified by a nondietary approach: genetic alteration of the protein BAD, which has known roles in regulating both apoptosis and glucose metabolism. When the metabolic function of BAD is genetically altered in mice, it produces reduced glucose and increased ketone body metabolism in neurons and astrocytes. This effect is related to regulation of BAD by phosphorylation and is independent of its apoptotic function. Mice with BAD modifications that produce decreased glucose metabolism exhibit a marked increase in the activity of neuronal ATP-sensitive potassium (KATP) channels and strong resistance to behavioral and electrographic seizures in vivo. This seizure resistance is lost upon genetic ablation of KATP channels, suggesting that KATP channels mediate BAD’s anticonvulsant effect.
Lactate Dehydrogenase
Authors: Sada Nagisa , Inoue Tsuyoshi 
Published: November 2017

Abstract
Glucose is transported into neurons and used as an energy source. It is also transported into astrocytes, a type of glial cell, and converted to lactate, which is then released to neurons and used as another energy source. The latter is called the astrocyte-neuron lactate shuttle. Although the lactate shuttle is a metabolic pathway, it also plays important roles in neuronal activities and brain functions. We recently reported that this metabolic pathway is involved in the antiepileptic effects of the ketogenic diet. Lactate dehydrogenase (LDH) is a metabolic enzyme that mediates the lactate shuttle, and its inhibition hyperpolarizes neurons and suppresses seizures. This enzyme is also a molecular target of stiripentol, a clinically used antiepileptic drug for Dravet syndrome. This review provides an overview of electrical regulation by the astrocyte-neuron lactate shuttle, and then introduces LDH as a metabolic target against epilepsy.
Overview of Ketone-Based Metabolism
Authors: D’Agostino Dominic P. 
Published: November 2017

Abstract
Nutritional ketosis produces a nonpathological hyperketonemia resulting from decreased glucose availability, lower insulin, and increased fat oxidation. However, the restrictive nature of the ketogenic diet (KD) has limited the clinical applicability of therapeutic ketosis, due to practical considerations. Emerging data suggests that many of the benefits of the KD are mechanistically attributable to the ketone bodies or specific medium chain triglycerides, and this has motivated investigators to develop strategies to further augment the efficacy of the KD or use metabolic-based supplements to circumvent the need for dietary restriction to improve compliance and the maintenance of this therapeutic state. This section, “Ketone-Based Metabolism: General Health and Metabolic Alternatives,” includes chapters that discuss the expanding medical and performance applications of nutritional ketosis and the emerging science of ketones and other related metabolites as alternative fuels and potent signaling molecules.
Identifying the Molecular Mechanism of the Medium Chain Triglyceride (Ketogenic) Diet
Authors: Walker Matthew C. , Williams Robin S.B. 
Published: November 2017

AbstractThe medium chain triglyceride (MCT) ketogenic diet provides a highly effective and commonly used approach for treating drug-resistant epilepsy. It is associated with elevated levels of two MCT-derived fatty acids, decanoioc and octanoic acids. Researchers have identified a role for decanoic acid and a range of novel related chemicals in seizure control in multiple acute in vitro and in vivo models. A principal mechanism of decanoic acid is direct inhibition of AMPA receptors, key excitatory neurotransmitter receptors widely recognized as a target for seizure control. These data suggest a therapeutic mechanism of the MCT ketogenic diet through a direct fatty acid–dependent mechanism, independent of ketosis. This discovery will enable the development of an improved and, potentially, better-tolerated diet and the generation of a corresponding pharmaceutical approach. The diet should be termed the MCT diet, as the consequent ketosis may not be necessary for seizure control.
Triheptanoin in Epilepsy and Beyond
Authors: Borges Karin 
Published: November 2017

AbstractTriheptanoin, the triglyceride of heptanoate (C7 fatty acid), is a novel treatment that is being used to treat patients with rare genetic metabolic disorders. When taken orally, triheptanoin is hydrolyzed in the gastrointestinal tract to heptanoate, which is thought to diffuse into the blood and body. Heptanoate and its liver ketone metabolites are then metabolized within cells to propionyl-CoA, which after carboxylation produces succinyl-CoA, resulting in anaplerosis—the refilling of a deficient tricarboxylic acid cycle. Here, data are summarized and discussed in relation to triheptanoin’s anticonvulsant effects in rodent seizure models. Biochemical data reveal that metabolic alterations found in brains of rodent seizure models can be restored by triheptanoin. Moreover, there are increasing preclinical and clinical studies indicating that triheptanoin is beneficial in other neurological and neuromuscular disorders, which are summarized here. Thus, triheptanoin seems to be a promising treatment for a variety of clinical conditions.
Interrelated concepts in the epidemiology of disease: Natural history and incubation period, time trends in populations, spectrum, iceberg, and screening
Authors: Bhopal Raj S. 
Published: November 2017

Abstract
The natural history of disease is the uninterrupted progression of disease from its initiation to either spontaneous resolution, containment by the body’s repair mechanisms, or to a clinically detectable problem. Related concepts include the changing pattern of disease in populations and levels of severity (spectrum) of disease. Often the number of cases identified is exceeded by those not discovered. An illustrative metaphor for this is the iceberg. The pyramid of disease develops this into a population concept. Screening is the application of tests to diagnose disease (or precursors) in an earlier phase of the natural history of disease, often in well people, or in a less severe part of the disease spectrum than is achieved in routine medical practice. The potential of screening is vast but there are important limitations, such as the inability to influence the natural history of many diseases.
Epidemiological study designs and principles of data analysis: A conceptually integrated suite of methods and techniques
Authors: Bhopal Raj S. 
Published: November 2017

Abstract
Epidemiological studies are unified by their common goals and by their basis in defined populations. The case series (or register-based study) includes examination of trends in deaths, cancers, notifiable diseases, and hospitalizations. Case–control studies are analysed by comparing the exposure to risk factors in cases to those in controls. In a population studied at a specific time and place (a cross-sectional study), measurements can be made of disease, the factors which may cause disease, or both simultaneously. Cohort studies produce data on disease incidence and are especially good on associations between risk factors and disease outcomes. Trials compare treated and untreated populations and are used, primarily, for information on effectiveness of health interventions. Natural experiments, including Mendelian randomization studies, may provide causal evidence. The principles for the analysis of all studies are similar. The design and interpretation should be in the context of traditional, systematic, and meta-analytic reviews.
Epidemiology in the past, present, and the future: Theory, ethics, context, and critical appraisal
Authors: Bhopal Raj S. 
Published: November 2017

Abstract
The philosophy and theory underpinning epidemiology is seldom made explicit but it is a positivist discipline. The basic theory is that systematic variations in the pattern of health and disease exist in populations and these are a product of differences in the prevalence of, or susceptibility to, the causal factors. Epidemiology using data on whole populations, comprising tens of millions, if not hundreds of millions of people, is on the horizon. Studies on billions of people may occur within this century. The health applications of epidemiology obligate a code of ethics and good conduct that serves both its scientific and its applied purposes. Ethical, professional, and social obligations also require epidemiologists to have an understanding of the wider determinants of health and disease and of the history of the discipline. Only then can a productive future be shaped.
Operationalizing patient-centredness to enhance recovery and primary care for mental disorders
Authors: Furler John , Palmer Victoria J. , Gunn Jane 
Published: November 2017

Abstract
Patient-centred practice has deep historical roots and offers exceptional potential in addressing the challenges of caring for people with mental disorders in primary care. In fact, primary care with its professional commitment to holistic care has been a champion and advocate for patient-centred practice. While the evidence base for patient centredness is complex, there are suggestions it can optimize some outcomes that are important to the notion of recovery in mental disorders. Patient centredness has been given new impetus as a model of care through its centrality in the Patient Centred Medical Home movement in the US, which in particular is trying to reintegrate care for mental disorders into generalist primary care, with an emphasis on safety and quality. Nevertheless, patient-centred practice is challenging and not without tensions. Particularly at an individual level, patient-centred practice is a socially contingent form of practice as much as a technical one. We describe how shared decision making gives insight into the need for specific strategies to ensure people with mental disorders receive recovery-oriented care. The chapter concludes by naming reflective practice as a key strategy in the operationalizing of patient-centred practice for mental disorders in primary care.
Neurobiology of psychiatric disorders
Authors: Maletic Vladimir , DeMuri Bernadette 
Published: November 2017

Abstract
Recent decades have witnessed a burgeoning multidisciplinary research into the neurobiological underpinning of major psychiatric disorders. Despite recent discoveries, our psychiatric taxonomy, and hence diagnosis, continues to be based on phenomenology. We have summarized some of the major advancements in our understanding of the role that genetics, functional and structural brain changes, alterations in neurotransmission and neuroplasticity, and cytopathology may play in etiopathogenesis of psychiatric disorders, particularly focusing on major depressive disorder and anxiety disorders. Furthermore, recent research has unequivocally implicated peripheral immune, endocrine, and autonomic changes in the pathophysiology of psychiatric disorders, not only as correlates but also as major factors involved in shaping the clinical expression of these conditions. Better understanding of the pathophysiology underlying psychiatric disorders may assist us in developing markers to help identify subtypes of these highly biologically and phenotypically heterogeneous conditions. Additionally, greater knowledge of etiological mechanisms may help us adopt more effective therapeutic approaches.
The DSM-5: What should general practitioners know?
Authors: Paris Joel 
Published: November 2017

Abstract
The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), was initially expected to be a radical revision of previous editions. However, there was insufficient evidence to support many of the proposals for changes, and the final product is not that different from DSM-IV. This having seen said, this chapter outlines what changes have been made, and what the future prospects for the classification of mental disorders may be.