A new way to produce hyperketonemia: use of ketone ester in a case of Alzheimer's disease.

BACKGROUND: Providing ketone bodies to the brain can bypass metabolic blocks to glucose utilization and improve function in energy-starved neurons. For this, plasma ketones must be elevated well above the ≤ 0.2 mM default concentrations normally prevalent. Limitations of dietary methods currently used to produce therapeutic hyperketonemia have stimulated the search for better approaches. METHOD: Described herein is a new way to produce therapeutic hyperketonemia, entailing prolonged oral administration of a potent ketogenic agent--ketone monoester (KME)--to a patient with Alzheimer's disease dementia and a pretreatment Mini-Mental State Examination score of 12. RESULTS: The patient improved markedly in mood, affect, self-care, and cognitive and daily activity performance. The KME was well tolerated throughout the 20-month treatment period. Cognitive performance tracked plasma ß-hydroxybutyrate concentrations, with noticeable improvements in conversation and interaction at the higher levels, compared with predose levels. CONCLUSION: KME-induced hyperketonemia is robust, convenient, and safe, and the ester can be taken as an oral supplement without changing the habitual diet.

Ketone body therapy: from the ketogenic diet to the oral administration of ketone ester.

Ketone bodies (KBs), acetoacetate and ß-hydroxybutyrate (ßHB), were considered harmful metabolic by-products when discovered in the mid-19th century in the urine of patients with diabetic ketoacidosis. It took physicians many years to realize that KBs are normal metabolites synthesized by the liver and exported into the systemic circulation to serve as an energy source for most extrahepatic tissues. Studies have shown that the brain (which normally uses glucose for energy) can readily utilize KBs as an alternative fuel. Even when there is diminished glucose utilization in cognition-critical brain areas, as may occur early in Alzheimer's disease (AD), there is preliminary evidence that these same areas remain capable of metabolizing KBs. Because the ketogenic diet (KD) is difficult to prepare and follow, and effectiveness of KB treatment in certain patients may be enhanced by raising plasma KB levels to ≥2 mM, KB esters, such as 1,3-butanediol monoester of ßHB and glyceryl-tris-3-hydroxybutyrate, have been devised. When administered orally in controlled dosages, these esters can produce plasma KB levels comparable to those achieved by the most rigorous KD, thus providing a safe, convenient, and versatile new approach to the study and potential treatment of a variety of diseases, including epilepsy, AD, and Parkinson's disease.

The mitochondrial permeability transition pore provides a key to the diagnosis and treatment of traumatic brain injury.

The pathological consequences of traumatic head injury result largely from the opening of the mitochondrial permeability transition pore (mPTP). The mPTP opens due to a decrease in brain phosphorylation energy resulting in a further decrease in brain ATP production and a measurable increase in brain heat generation and temperature. The increase in brain temperature can be measured transcranially by near infrared spectroscopy which can be used to diagnose traumatic brain injury (TBI) and to monitor treatment. Effective therapy of TBI can be achieved by closure of the mPTP by administration of cyclosporine A or by oral administration of ketone body esters. While ketosis has previously been known to prevent damage from TBI, the availability of oral ketone esters presents the first practical modality of achieving therapeutic levels of ketone bodies.

Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects.

Induction of mild states of hyperketonemia may improve physical and cognitive performance. In this study, we determined the kinetic parameters, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, a ketone monoester administered in the form of a meal replacement drink to healthy human volunteers. Plasma levels of ß-hydroxybutyrate and acetoacetate were elevated following administration of a single dose of the ketone monoester, whether at 140, 357, or 714 mg/kg body weight, while the intact ester was not detected. Maximum plasma levels of ketones were attained within 1-2h, reaching 3.30 mM and 1.19 mM for ß-hydroxybutyrate and acetoacetate, respectively, at the highest dose tested. The elimination half-life ranged from 0.8-3.1h for ß-hydroxybutyrate and 8-14 h for acetoacetate. The ketone monoester was also administered at 140, 357, and 714 mg/kg body weight, three times daily, over 5 days (equivalent to 0.42, 1.07, and 2.14 g/kg/d). The ketone ester was generally well-tolerated, although some gastrointestinal effects were reported, when large volumes of milk-based drink were consumed, at the highest ketone monoester dose. Together, these results suggest ingestion of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate is a safe and simple method to elevate blood ketone levels, compared with the inconvenience of preparing and consuming a ketogenic diet.

Traumatic brain injury (TBI) in collision sports: Possible mechanisms of transformation into chronic traumatic encephalopathy (CTE).

Traumatic brain injury (TBI) is a leading cause of death and disability, contributing to ~30% of all injury-related deaths in the US. TBI occurs when a force transmitted to the head causes neuropathologic damage and impairment of brain function. TBI doubles risk of suicide and is the major determinant of acquired seizure disorders. TBI arising from closed head trauma (CHT) significantly increases the risk of developing Alzheimer's disease (AD), Parkinson's disease (PD) and chronic traumatic encephalopathy (CTE). Evidence for a possible role of TBI as a risk factor for sporadic amyotrophic lateral sclerosis (sALS) has been provided by studies of professional players of European football. Depending on age, genetic make-up (in particular, being a carrier of one or two ApoE4 alleles), the number of TBIs sustained, their severity, the time periods involved, and many other factors that affect vulnerability, decades may pass after occurrence of one or more TBIs before sequelae such as AD, PD, sALS or CTE become clinically evident. Among college and professional football players who experience repeated concussions and sub-concussive blows to the head, the risk of developing CTE increases with the number of years actively devoted to the sport, and the degree of exposure to physical impacts inherent in the position played. Following a moderate or severe concussion, or a series of mild blows to the head, the brain may undergo subtle pathophysiological changes that are unlikely to be detected with confidence using available diagnostic methods. Biomarkers are being sought that can help the attending physician infer the likely presence of an ongoing occult neurodegenerative process. One example of the adverse effect of collision on the brain is "heading" the soccer ball-a feat that, repeated over years of competition, has been found to produce severe brain damage in veteran players. CTE has attracted increasing national attention because of its devastating effects in a high proportion of retired professional players of American football. In a study of brains from deceased former football players, contributed mostly by family members, CTE was neuropathologically diagnosed in 110 of 111 of National Football League (NFL) veterans. In the CTE-positive subjects, the authors observed extensive brain atrophy, astrogliosis, myelinated axonopathy, microvascular injury, perivascular neuroinflammation, and phosphorylated tau protein pathology. CTE's neuropathology has been formally defined as a tauopathy characterized by a distinct perivascular accumulation of hyperphosphorylated tau in neurons and astrocytes within cerebral sulci. Although the mechanism that underlies the unforeseen emergence of CTE long after the occurrence of one or more closed head traumas is unknown, an explanation proposed by Albayram and associates is persuasive. They discovered TBI-induced neuronal production of the toxic compound cis P-tau, an abnormal and destructive isomer of the normal and benign trans P-tau, in mouse models of CTE. Cis P-tau produced a CTE-like syndrome via a process they termed cistauosis. Cistauosis can be blocked in laboratory animals by cis P-tau monoclonal antibody, which prevents later development of tau tangles, brain atrophy and virtual CTE. In a subsequent study, the same group found in human samples obtained post-TBI from a variety of causes, that cis P-tau is induced in cortical axons and cerebrospinal fluid and positively correlates with axonal injury and clinical outcome. Thus, cis P-tau appears to contribute to short-term and long-term sequelae after TBI, but may be subject to neutralization by cis-antibody treatment.

Alzheimer's disease: Innate immunity gone awry?

Inflammation is an immune activity designed to protect the host from pathogens and noxious agents. In its low-intensity form, presence of an inflammatory process must be inferred from appropriate biomarkers. Occult neuroinflammation is not just secondary to Alzheimer's disease (AD) but may contribute to its pathogenesis and promote its progression. A leaky blood-brain barrier (BBB) has been observed in early AD and may play a role in its initiation and development. Studies of the temporal evolution of AD's biomarkers have shown that, in AD, the brain's amyloid burden correlates poorly with cognitive decline. In contrast, cognitive deficits in AD correlate well with synapse loss. Oligomeric forms of amyloid-beta (oAßs) can be synaptotoxic and evidence of their deposition inside synaptic terminals of cognition-associated neurons explains early memory loss in AD better than formation of extracellular Aß plaques. Among innate immune cells that reside in the brain, microglia sense danger signals represented by proteins like oAß and become activated by neuronal damage such as that caused by bacterial endotoxins. The resulting reactive microgliosis has been implicated in generating the chronic form of microglial activation believed to promote AD's development. Genome-wide association studies (GWASs) have yielded data from patients with sporadic AD indicating that its causes include genetic variation in the innate immune system. Recent preclinical studies have reported that ß-hydroxybutyrate (ßOHB) may protect the brain from the adverse effects of both the nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome and the deacetylation of histone. Consequently, there is an urgent need for clinical investigations designed to test whether an orally administered ßOHB preparation, such as a ketone ester, can have a similar beneficial effect in human subjects.

Sleep and energy balance: Interactive homeostatic systems.

For early humans, acquisition of food by hunting and/or gathering was a hunger-driven process requiring vigilance and (often) strenuous physical effort during daylight hours. To sustain such activities, hunter-gatherers also needed periodic rest and sleep-pursuits most effectively undertaken at night. In recent years, research has given us new insights into the physiologic underpinnings of these behaviors. Specifically, evidence has been uncovered indicating that the homeostatic regulation of food intake on the one hand and that of sleep on the other hand, are intertwined. Thus, carefully performed studies of eating behavior in rats indicate that duration of sleep after ingestion of a meal is closely correlated to the meal's energy content. In 1999, it was discovered that mice and dogs functionally deficient in the appetite-stimulating hormone, hypocretin-1, become narcoleptic, suggesting the existence of a "hard-wired" connection between regulation of hunger and satiety and regulation of sleep. Administered into the nucleus accumbens shell, hypocretin-1 induces feeding and locomotor activity in Sprague-Dawley rats. Hypocretin neurons in the hypothalamus are responsive to metabolic cues capable of signaling nutritional status. The suprachiasmatic nucleus, the body's principal circadian clock, exchanges information with the hypocretin system about the light/dark cycle and the body's metabolic condition. Circadian Clock mutant mice exhibit an attenuated diurnal feeding rhythm and become hyperphagic and obese. Both disruption of the circadian cycle and sleep deprivation can affect energy balance and, over time, may bring about substantial changes in body composition. Although there is growing evidence that interleukin-6 and several other proinflammatory cytokines are "sleep factors" that also affect energy balance, any possible role they might have in coordinating sleep/wakefulness with food-motivated behavior awaits clarification. Yet, the evidence is increasingly strong that the neurophysiologic and metabolic mechanisms responsible for the control of food-seeking behavior and the control of sleep and wakefulness are coordinated so that hunger and vigilance are paired during the daylight hours, and satiety and sleep are paired during darkness. The hypothalamic neuronal system that links these mechanisms is predominantly, but not exclusively, hypocretinergic, and is responsive to the suprachiasmatic nucleus circadian pacemaker and to certain metabolic signals of depletion and repletion.

Subsyndromal depression in the elderly: underdiagnosed and undertreated.

Major depressive illness is present in about 5.7% of US residents aged>or=65 years, whereas clinically significant nonmajor or "subsyndromal" depression affects approximately 15% of the ambulatory elderly. Risk of developing subsyndromal depression increases as elderly people get older. Because they have numerous distressing ailments, everyday life can be burdensome for many elderly persons. Almost one third of Americans aged 75 years or older rate their health as "fair to poor." Yet, the physical discomforts experienced by so many elderly individuals are unlikely to generate a clinically significant depression unless other ingredients such as loneliness, impairment of mobility, loss of a spouse, a serious financial reverse, and--probably most important--genetic susceptibility are added to the psychophysiological mix. Because depression damages quality of life and is usually eminently treatable, it is essential that physicians and other health professionals be trained to recognize true depression and distinguish it from confounding conditions caused by medications, organic brain disease, or short-term grief reactions. In the medically ill elderly, depressive symptoms may be overlooked because of the assumption that they are a part of the concurrent medical illness. Diagnosis of depression in the elderly can be greatly assisted by use of age-specific screening instruments such as the Geriatric Depression Scale. Ultimately, brain imaging and biochemical and physiological measurements may prove useful in diagnosis. The presence of somatic concomitants of depression such as severe neck and low back pain should alert the clinician to the possibility of an underlying mood disorder. Suicide and suicide attempts occur all too frequently in the depressed elderly; therefore, screening for late-life depression is urgently required among the elderly in primary and residential health care settings.

The escalating pandemics of obesity and sedentary lifestyle. A call to action for clinicians.

Obesity and sedentary lifestyle are escalating national and global epidemics that warrant increased attention by physicians and other health care professionals. These intricately linked conditions are responsible for an enormous burden of chronic disease, impaired physical function and quality of life, at least 300,000 premature deaths, and at least $90 billion in direct health care costs annually in the United States alone. Clinicians are on the front line of combat, yet these conditions receive minimal attention during a typical office visit. Clinicians often feel overwhelmed by these challenges and point to an absence of clear guidelines and practice tools, minimal training in behavior modification strategies, and lack of time as reasons for failing to confront them. This report provides a "call to action" with step-by-step guidelines specifically directed at the pivotal role of physicians and other health care professionals in curbing these dangerous epidemics. This blueprint for action, which requires only a few minutes of a clinician's time to implement, will facilitate more effective intervention related to obesity and inactivity and should favorably impact public health.

Biomarkers, ketone bodies, and the prevention of Alzheimer's disease.

Sporadic Alzheimer's disease (spAD) has three successive phases: preclinical, mild cognitive impairment, and dementia. Individuals in the preclinical phase are cognitively normal. Diagnosis of preclinical spAD requires evidence of pathologic brain changes provided by established biomarkers. Histopathologic features of spAD include (i) extra-cellular cerebral amyloid plaques and intracellular neurofibrillary tangles that embody hyperphosphorylated tau; and (ii) neuronal and synaptic loss. Amyloid-PET brain scans conducted during spAD's preclinical phase have disclosed abnormal accumulations of amyloid-beta (Aß) in cognitively normal, high-risk individuals. However, this measure correlates poorly with changes in cognitive status. In contrast, MRI measures of brain atrophy consistently parallel cognitive deterioration. By the time dementia appears, amyloid deposition has already slowed or ceased. When a new treatment offers promise of arresting or delaying progression of preclinical spAD, its effectiveness must be inferred from intervention-correlated changes in biomarkers. Herein, differing tenets of the amyloid cascade hypothesis (ACH) and the mitochondrial cascade hypothesis (MCH) are compared. Adoption of the ACH suggests therapeutic research continue to focus on aspects of the amyloid pathways. Adoption of the MCH suggests research emphasis be placed on restoration and stabilization of mitochondrial function. Ketone ester (KE)-induced elevation of plasma ketone body (KB) levels improves mitochondrial metabolism and prevents or delays progression of AD-like pathologic changes in several AD animal models. Thus, as a first step, it is imperative to determine whether KE-caused hyperketonemia can bring about favorable changes in biomarkers of AD pathology in individuals who are in an early stage of AD's preclinical phase.

Ketones: metabolism's ugly duckling.

Ketones were first discovered in the urine of diabetic patients in the mid-19th century; for almost 50 years thereafter, they were thought to be abnormal and undesirable by-products of incomplete fat oxidation. In the early 20th century, however, they were recognized as normal circulating metabolites produced by liver and readily utilized by extrahepatic tissues. In the 1920s, a drastic "hyperketogenic" diet was found remarkably effective for treatment of drug-resistant epilepsy in children. In 1967, circulating ketones were discovered to replace glucose as the brain's major fuel during the marked hyperketonemia of prolonged fasting. Until then, the adult human brain was thought to be entirely dependent upon glucose. During the 1990s, diet-induced hyperketonemia was found therapeutically effective for treatment of several rare genetic disorders involving impaired neuronal utilization of glucose or its metabolic products. Finally, growing evidence suggests that mitochondrial dysfunction and reduced bioenergetic efficiency occur in brains of patients with Parkinson's disease (PD) and Alzheimer's disease (AD). Because ketones are efficiently used by mitochondria for ATP generation and may also help protect vulnerable neurons from free radical damage, hyperketogenic diets should be evaluated for ability to benefit patients with PD, AD, and certain other neurodegenerative disorders.

Stress: a risk factor for serious illness.

The body's principal adaptive responses to stress stimuli are mediated by an intricate stress system, which includes the hypothalamic-pituitary-adrenocortical (HPA) axis and the sympathoadrenal system (SAS). Dysregulation of the system, caused by the cumulative burden of repetitive or chronic environmental stress challenges (allostatic load) contributes to the development of a variety of illnesses including hypertension, atherosclerosis, and the insulin-resistance-dyslipidemia syndrome, as well as certain disorders of immune function. The brain's limbic system, particularly the hippocampus and amygdala, is also intimately involved in the stress response. Chronically elevated corticosteroid levels induced by persisting stress may adversely affect hippocampal structure and function, producing deficits of both memory and cognition. The ability of stress to cause illness in humans is most clearly exemplified by post-traumatic stress disorder (PTSD), which consists of a predictable constellation of distressing behavioral symptoms and physiological features. An appreciable proportion of the observed variance in vulnerability to PTSD is attributable to genetic factors. The relationship of this disorder to its precipitating cause-a recent, severely traumatic event-is unambiguous. The neuroendocrinology of PTSD is noteworthy, being characterized in many adult victims by enhanced negative feedback sensitivity of glucocorticoid receptors in the stress response system, and lower than normal urinary and plasma cortisol levels. Adult patients with PTSD also have been shown to exhibit exaggerated catecholamine responses to trauma-related stimuli. On the other hand, severely maltreated prepubertal children with PTSD continue to excrete greater than normal urinary cortisol, catecholamines, and dopamine years after disclosure of the causative abuse.

Frailty in the elderly: contributions of sarcopenia and visceral protein depletion.

In any given population of free-living individuals 65 years of age and older, a substantial proportion (in the range of 6% to 25%) suffers from many of the elements of the syndrome of frailty. Although the syndrome is complex and still lacks a standard definition, there is a growing consensus about the signs and symptoms as well as the pattern of biological correlates that characterize this disorder. Patients who are afflicted with frailty typically exhibit loss of muscle strength, fatigue easily, are physically inactive, and have a slow-and often unsteady-gait, with an increased risk (and fear) of falling. They are likely to have a poor appetite and to have undergone a recent, unintentional loss of weight. Frail individuals are more likely than the nonfrail to experience impaired cognition and depression. They die sooner. Frailty, of course, is frequently complicated by a variety of coexistent illnesses. Among the biological correlates of frailty are sarcopenia (now readily measurable by dual-energy x-ray absorptiometry [DXA]), osteopenia (with an increased susceptibility to fracture), and activation of the inflammatory and coagulation systems, with a rise in inflammatory cytokines and several markers of coagulopathy. Age-dependent changes in a number of hormones also appear to promote the development of frailty in the elderly, particularly via their effects on muscle mass and strength, bone density, and by contributing to activation of the catabolic cytokines. In particular, serum levels of growth hormone (GH) and insulin-like growth factor-1 (IGF-1) decline progressively during aging, and an association between reduction in the levels of these hormones and the involution of advancing age has been proposed. It is not yet known whether, in comparison with their nonfrail counterparts, frail individuals consistently manifest larger reductions in GH and IGF-1 (and other anabolic hormones). More research is needed before it will be known whether the benefits of administering GH to the frail elderly will outweigh the disadvantages. The poor appetite and weight loss that occur in many frail individuals are likely to be accompanied by a degree of visceral protein depletion (with its attendant morbidity), which can be estimated by making serial measurements of indicators of visceral protein status such as transthyretin (TTR), retinol-binding protein (RBP), and albumin. One characteristic of the frailty syndrome that distinguishes it from the effects of aging per se is the potential reversibility of many of its features. Progressive resistance training is feasible for many elderly individuals-even the oldest old-and, by increasing muscle mass and strength, can ameliorate or reverse important aspects of physical frailty. To the extent that visceral protein depletion has been caused by an inadequate intake of calories and protein, consumption of a more adequate diet can result in betterment of the frail patient's nutritional status, as determined by clinical improvement and favorable changes in TTR, RBP, and albumin.

Preclinical sporadic Alzheimer's disease: target for personalized diagnosis and preventive intervention.

The most opportune time for preventive intervention in sporadic Alzheimer's disease (spAD) is early in its preclinical stage (pcAD), when the odds of preventing or minimizing later disabling neurodegeneration are most favorable. The efficacy of promising preventive interventions should be assessed in patients in the earliest discernible phase of pcAD. This will require application of personalized medicine techniques, with use of suitable biomarkers to detect pcAD in individuals believed to be spAD-prone. This review focuses on the genetic biomarker, apolipoprotein E (apoE) ε4, and on certain neuroimaging biomarkers, such as structural MRI (sMRI), fluorodeoxyglucose-positron emission tomography (FDG-PET), and PET-amyloid tracers capable of delineating the extent and distribution of amyloid-beta (Aß) deposits in the brain, that can be useful in identifying cognitively normal people who are at enhanced risk of developing spAD. Many years before AD symptoms appear, such neuroimaging procedures can disclose signature abnormalities of brain structure, function, and amyloid levels in cognitively normal apoE ε4 allele carriers and/or individuals with a family history of spAD. Although no effective treatment for spAD is yet available, there is evidence that, by taking a proactive personalized-medicine approach, the practicing physician may be able to reduce risk in AD-prone patients by attending to such modifiable AD risk factors as hypertension, obesity, type 2 diabetes, insulin resistance, hypercholesterolemia, sedentary lifestyle, and current cigarette smoking. Young patients who are ε4 positive should be advised to avoid participation in contact sports or other activities that expose them to risk of traumatic brain injury.

Gout: epitome of painful arthritis.

Arthritic pain and disability are at or near the top of the list of reasons adult patients seek medical attention. At least 47.8 million US residents have arthritis. In Europe, the magnitude of the problem is similar, affecting 8 million in the United Kingdom and 108 million across the continent. Osteoarthritis is by far the most common form of arthritis. In a regional UK study, nearly half of adults 50 years or older reported some form of osteoarthritic knee pain over a 1-year period. Among the arthritides, gout is notable for the agonizing nature and unique pathogenesis of the pain it generates. Gout is the most common cause of inflammatory arthritis among men and postmenopausal women. Because of the atypical nature of some of its clinical manifestations, gout can present serious diagnostic challenges for practicing physicians. In recent years, knowledge about gout's pathogenesis, pathophysiology, and differential diagnosis has advanced on a broad front. Genetic variants within a newly identified transport gene, SLC2A9, have been associated with a low fractional excretion of uric acid and the presence of gout in several population samples. The SLC2A9 gene encodes glucose transporter 9-a unique hexose and high-capacity urate transporter. In addition, human ATP-binding cassette, subfamily G2 (ABCG2), encoded by the ABCG2 gene, has been found to mediate renal urate secretion. Introduction of a mutation encoded in a model system by a common single nucleotide polymorphism, rs2231142, resulted in a 53% reduction in urate transport rates compared with wild-type ABCG2. Based on a large population study, it has been estimated that at least 10% of all gout cases in white persons may be attributable to this single nucleotide polymorphism causal genetic variant. Of the various categories of arthritis, the crystal-induced arthropathies, gout and pseudogout, are manifested by acute inflammation and tissue damage arising from deposition in joints and periarticular tissues of monosodium urate (MSU), calcium pyrophosphate dehydrate, or basic calcium phosphate crystals. The innate immune system rapidly detects invading pathogenic microbes and nonmicrobial "danger signals" such as MSU crystals. When these crystals are deposited in synovial tissues, NLR proteins (NOD-like receptors) form multiprotein complexes known as inflammasomes that trigger secretion of inflammation-producing cytokines like interleukin-1ß and interleukin-18. Usually, gout can be diagnosed by medical history, physical examination, and presence of hyperuricemia (urate >416 µmol/L). However, a urate concentration less than 416 does not by itself rule out gout. Confirmation of the diagnosis by identification of typical MSU crystals in aspirated synovial fluid is definitive. Analysis of joint fluid is mandatory to rule out septic arthritis, which can rapidly become lethal. Because of its special ability to identify and quantitate urate deposits in peripheral tissues, dual-energy computed tomography should prove valuable in the differential diagnosis of gout. Gout mimics a variety of illnesses; for example, spinal gout may masquerade as metastatic cancer, epidural abscess, and nerve compression syndrome.

Opioids for cancer pain: the challenge of optimizing treatment.

During 2007, 11.7 million US men and women of all ages suffered from some form of invasive cancer. During their illness, at least 70% (8.2 million) will experience pain sufficiently severe to require chronic opioid treatment. Cancer-induced pain is usually described under 3 headings: acute pain, chronic pain, and breakthrough pain. Among patients with chronic, persistent cancer pain controlled by around-the-clock analgesics, there is a high prevalence of breakthrough pain-often precipitated by some form of physical activity. Breakthrough pain seems best treated by a powerful, fast-acting opioid such as intravenous morphine or transmucosal fentanyl. At present, opioids are virtually the only analgesics capable of controlling moderate and severe cancer pain. In recent years, a veritable arsenal of opioids with a wide range of pharmacologic properties has become available for use in different pain situations. The World Health Organization has developed a 3-step "analgesic ladder" to guide management of cancer pain, based on the pain's severity, estimated by means of a 1 to 10 numeric rating scale. As the severity of the pain escalates, more potent (World Health Organization Step III) opioids are used. When faced with a difficult case of cancer pain, the physician must choose-from an array of options-the safest and most effective opioid analgesic and the most appropriate delivery system. Such decisions require an adequate understanding of the available opioids and experience with their use. The pharmacodynamic response to a given opioid depends on the nature of the receptor to which the opioid binds and its affinity for the receptor. Morphine activates the µ-opioid receptors, resulting in not only analgesia and sedation, but also euphoria, respiratory depression, constipation, and pruritus. The existence of a number of opioid receptor subtypes, each with its own repertoire of responses, has given rise to the hope (as yet unrealized) that an opioid can be found (or engineered) that will selectively produce adequate analgesia and sedation without, at the same time, causing unwanted adverse effects. Furthermore, suitable neurostimulatory or neuroinhibitive methods involving the central nervous system are being sought that can amplify the analgesic action of opioids. In the search for antinociceptive agents as efficacious as currently available opioids, but without their troublesome adverse effects, the endogenous opioids, such as the endomorphins, are being examined as offering possible solutions to the adverse effect problem.

Parkinson disease: primacy of age as a risk factor for mitochondrial dysfunction.

In 1983, it was reported that certain drug users with a history of exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a contaminant of an illicitly produced meperidine analogue, developed an irreversible syndrome resembling idiopathic Parkinson disease (PD). Soon thereafter, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine's active metabolite, 1-methyl-4-phenylpyridine, was shown to be a complex I inhibitor. Activity of complex I (the point of entry for most electrons that traverse the mitochondrial electron transport chain) has been found to be impaired in the substantia nigra pars compacta and also in other brain tissues in PD patients. In 2006, high temporal and spatial resolution phosphorous functional magnetic resonance spectroscopy was used to demonstrate that, in 20 PD patients, mitochondrial dysfunction extended to the visual cortex. Epidemiologic studies have implicated a number of apparently disparate exogenous factors in the causation of PD. For example, exposure to certain pesticides and herbicides (many known to inhibit electron transport chain activity) increases PD risk. Parkinson disease risk can be doubled, tripled, or more in individuals with repeated head injuries. Over time, PD risk is almost doubled in men and women with prior type 2 diabetes mellitus. Nevertheless, despite evidence that certain exogenous and/or developmental factors play a role in causation of PD, their potential effect on PD incidence is greatly overshadowed by that of advancing age. In 1 prospective study, PD incidence rate in subjects at least 85 years old was about 14 times that observed in subjects aged 56 to 65 years. The dramatic effect of aging on PD risk may be explained in part by the fact that mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra pars compacta neurons. High levels of these mutations are associated with electron transport chain deficiency, a situation that favors increased oxidative damage, Lewy body formation, and apoptotic cell death. Systematic study of the effects of putative risk factors in animal models of parkinsonism may be expected to improve our understanding of PD's complex pathogenesis.