Potential Non-neoplastic Applications for Polyphenols in Stem Cell Utilization.

While polyphenols may have important effects on pluripotential stem cells that make them noteworthy as potential antineoplastic agents, their action on stem cells may portend other health benefits, such as treatments for cardiovascular and neurocognitive disorders. Resveratrol, the beststudied polyphenol, has been found to enable stem cells to differentiate into cardiomyocytes, neurons, osteocytes, and pancreatic beta cells, as well as facilitating augmentation of stem cell populations and protecting them from toxic injury. Curcumin protects mesenchymal stem cells from toxicity, and prevents them from facilitating chondrocytic hypertrophy. Quercetin enabled osteocytic and pancreatic beta cell differentiation, and protected neuronal stem cells from injury. Epigallocatechin gallate prevented damage to osteocyte precursors and averted differentiation into undesirable adipocytes. Genistein facilitated osteogenesis while preventing adipogenesis. Several other polyphenols, daidzein, caffeic and chlorogenic acid, kaempferol, and piceatannol, protect stems cells from reactive oxygen species and foster stem cells differentiation away from adipocytic and toward osteocytic lineages. Further research should better elucidate the pharmacokinetic profiles of each polyphenol, explore novel delivery systems, and expand investigation beyond rodent models to additional species.

To bee or not to bee: The potential efficacy and safety of bee venom acupuncture in humans.

Bee venom acupuncture is a form of acupuncture in which bee venom is applied to the tips of acupuncture needles, stingers are extracted from bees, or bees are held with an instrument exposing the stinger, and applied to acupoints on the skin. Bee venom is a complex substance consisting of multiple anti-inflammatory compounds such as melittin, adolapin, apamin. Other substances such as phospholipase A2 can be anti-inflammatory in low concentrations and pro-inflammatory in others. However, bee venom also contains proinflammatory substances, melittin, mast cell degranulation peptide 401, and histamine. Nevertheless, in small studies, bee venom acupuncture has been used in man to successfully treat a number of musculoskeletal diseases such as lumbar disc disease, osteoarthritis of the knee, rheumatoid arthritis, adhesive capsulitis, and lateral epicondylitis. Bee venom acupuncture can also alleviate neurological conditions, including peripheral neuropathies, stroke and Parkinson's Disease. The treatment has even been piloted in one series to alleviate depression. An important concern is the safety of bee venom. Bee venom can cause anaphylaxis, and several deaths have been reported in patients who successfully received the therapy prior to the adverse event. While the incidence of adverse events is unknown, the number of published reports of toxicity is small. Refining bee venom to remove harmful substances may potentially limit its toxicity. New uses for bee venom acupuncture may also be considered.

The Potential Effects of Caffeinated Beverages on Insulin Sensitivity.

Caffeinated beverages, most commonly tea and coffee, may have important effects on insulin regulation that may give their consumption an important role among nutritional factors in the development of diseases of glucose and insulin metabolism, such as diabetes and atherosclerotic vascular diseases. These beverages include compounds that may have contradictory effects on insulin and glucose: Caffeine impairs insulin sensitivity, but polyphenolic molecules within tea, coffee, and cocoa augment the effects of insulin. In addition, epidemiologic associations exist between greater consumption of such beverages and lower risk of diabetes. The beneficial effects of such beverages might be enhanced by changing the process of their preparation and substitution of other substances commonly added to caffeinated beverages that impair the effect of insulin, such as sugar or milk.

The benefit of pets and animal-assisted therapy to the health of older individuals.

Many studies utilizing dogs, cats, birds, fish, and robotic simulations of animals have tried to ascertain the health benefits of pet ownership or animal-assisted therapy in the elderly. Several small unblinded investigations outlined improvements in behavior in demented persons given treatment in the presence of animals. Studies piloting the use of animals in the treatment of depression and schizophrenia have yielded mixed results. Animals may provide intangible benefits to the mental health of older persons, such as relief social isolation and boredom, but these have not been formally studied. Several investigations of the effect of pets on physical health suggest animals can lower blood pressure, and dog walkers partake in more physical activity. Dog walking, in epidemiological studies and few preliminary trials, is associated with lower complication risk among patients with cardiovascular disease. Pets may also have harms: they may be expensive to care for, and their owners are more likely to fall. Theoretically, zoonotic infections and bites can occur, but how often this occurs in the context of pet ownership or animal-assisted therapy is unknown. Despite the poor methodological quality of pet research after decades of study, pet ownership and animal-assisted therapy are likely to continue due to positive subjective feelings many people have toward animals.

The use of shared medical appointments in the care of the elderly.

The shared medical appointment is a model of delivering outpatient care in which several patients interact simultaneously with 1 or several providers. These appointments were developed as an efficient means of delivering education about chronic medical conditions to elderly individuals. In several, but not all trials, chronically ill elderly and younger patients have achieved better general and disease-specific outcomes. However, because the studies have compared these appointments with conventional care, it is not clear whether advantages occur because of the unique characteristics of such an outpatient visit or because of more time spent or greater numbers of providers interacting with patients.

Use of complementary and alternative medicine to treat constipation in the elderly.

Many modalities of complementary and alternative medicine, such as probiotic bacteria, traditional herbal medicines, biofeedback and massage, have been used to treat constipation in older adults. Virtually all studies in the published literature have been plagued with methodological problems, such as lack of blinding. Chinese herbal medications have been the most frequent subject of studies in controlled trials, but have suffered from methodological insufficiencies, and few have been published in publications other than Chinese language journals. Several therapies, such as yogurt containing probiotic bacteria and massage, are relatively easy to use by the patient, and are likely to cause few adverse reactions. Therefore, complementary and alternative therapies might show the greatest promise for being adopted as adjunctive therapies to conventional treatment.

A berry thought-provoking idea: the potential role of plant polyphenols in the treatment of age-related cognitive disorders.

Today, tens of millions of elderly individuals worldwide suffer from dementia. While the pathogenesis of dementia is complex and incompletely understood, it may be, at least to a certain extent, the consequence of systemic vascular pathology. The metabolic syndrome and its individual components induce a proinflammatory state that damages blood vessels. This condition of chronic inflammation may damage the vasculature of the brain or be directly neurotoxic. Associations have been established between the metabolic syndrome, its constituents and dementia. A relationship has also been observed between certain dietary factors, such as constituents of the 'Mediterranean diet', and the metabolic syndrome; similar associations have been noted between these dietary factors and dementia. Fruit juices and extracts are under investigation as treatments for cognitive impairment. Blueberry, strawberry, blackberry, grape and plum juices or extracts have been successfully tested in cognitively impaired rodents. Published trials of the benefits of grape and blueberry juice in the treatment of small numbers of cognitively impaired persons have recently appeared. The benefits of fruit products are thought to be a result of its polyphenol content. A grape polyphenol found in grapes, resveratrol, now being studied in humans, and one in grapes and blueberries, pterostilbene, have been found to improve cognition in rodents. In the design of future human trials, one ought to consider the poor bioavailability of these products, the possible need to initiate the experimental therapy long before the onset of symptoms, and currently limited knowledge about the appropriate form (e.g. juice, powder or individual polyphenol) of treatment.

Ergogenic dietary aids for the elderly.

Ergogenic dietary aids might be useful adjunctive therapy to enhance the effects of exercise in the elderly, who lose physical function with age. Many such aids have been tested in athletes and untrained younger persons in laboratory and athletic performance settings, with positive results, although not all studies have demonstrated benefit. Some substances have been tested in the elderly, including creatine, caffeine, ß-hydroxy-ß-methylbutyrate, ubiquinone, and carnitine. The published medical evidence for the use of these substances is considered in this review article. All studies have involved a few subjects for a short period. Studies of creatine alone or together with exercise in old persons have yielded mixed results. These studies have confirmed that creatine in older individuals, as in younger individuals, can increase the short-term capacity to perform quick, repeated episodes of intense activity. An investigation of caffeine has suggested that in older as in younger individuals, caffeine increases endurance but may not improve other parameters of exercise capacity. Evidence has implied ß-hydroxy-ß-methylbutyrate can increase the ability to perform certain short-term activities requiring strength, but not others. Carnitine has been reported to decrease fatigue and increase endurance in older persons. An investigation of ubiquinone has shown no benefit. Further testing has involved the combinations of agents, such as creatine and caffeine, and combinations of ß-hydroxy-ß-methylbutyrate, showing some small improvements in physical function. Future research with these and potentially other combinations over a longer duration will be needed to establish the safety and efficacy of ergogenic dietary aids.

Complementary medicine use is not associated with non-adherence to conventional medication in the elderly: a retrospective study.

Lack of adherence to medications is a potential cause of hospitalizations, morbidity, and mortality in the elderly. Medication adherence decreases with polypharmacy. Older persons commonly use complementary medicine, therefore complementary medicine use might pose an increase risk of loss of medication adherence with conventional medications, but this has not been previously investigated. A chart review was conducted of 300 patients at least sixty-five years of age who used at least three medications each who attended a university geriatrics clinic in Florida, USA to obtain information about medication adherence and complementary medicine use. However, no association was found between use of at least one complementary medicine and adherence to conventional medications.

Polyphenols: planting the seeds of treatment for the metabolic syndrome.

Greater understanding about the pathogenesis of metabolic syndrome and potential causes suggests that plant polyphenols might be useful as a treatment. Dietary excess energy can be stored in adipocytes, leading to the release of proinflammatory cytokines and adipose-related hormones that cause vascular injury. Plant polyphenols, organic compounds found in numerous plant species and their fruits, are being actively studied as potential treatments for components of the metabolic syndrome. Individual polyphenols that have been examined include resveratrol, quercetin, epigallocathechin-3-gallate, and curcumin. Resveratrol lowers weight, blood pressure, glucose, and insulin resistance in rodents, and a human trial is currently underway. Quercetin decreases lipid and glucose levels in obese rats, and in a human investigation of subjects with the metabolic syndrome has lowered blood pressure without significant alteration of lipids. Epigallocathechin-3-gallate-induced weight loss has attenuated glucose levels and insulin resistance in rodents and improved hemoglobin A(1c) and lipid in human studies. Plant extracts also can be used. Grape seed and chokeberry extracts have decreased blood pressure and lipid levels in small human trials. Other human investigations have shown the beneficial effects of cocoa, coffee, carob, and Momordica charantia. Thus far, most studies have involved a small number of subjects and have been of short duration. Future studies should be designed to account for a disease process in which the pathogenic factors may take place for years before disease manifestations take place, the possibly limited bioavailability of polyphenols, and the potential need to provide combinations or modifications of polyphenols.

Bugs as drugs, part two: worms, leeches, scorpions, snails, ticks, centipedes, and spiders.

In this second of a two-part series analyzing the evidence for the use of organisms as medicine, the use of a number of different "bugs" (worms, leeches, snails, ticks, centipedes, and spiders) is detailed. Several live organisms are used as treatments: leeches for plastic surgery and osteoarthritis and the helminths Trichuris suis and Necator americanus for inflammatory bowel disease. Leech saliva is the source of a number of anticoagulants, including the antithrombin agent hirudin and its synthetic analogues, which have been approved for human use. Predatory arthropods, such as certain species of snails, spiders, scorpions, centipedes, and ticks provide a trove of potential analgesic peptides in their venom. A synthetic analogue of a snail venom peptide, ziconotide, has been approved for human use and is used as an alternative to opioids in severe pain cases. Arthropods, such as ticks, have venom that contains anticoagulants and centipede venom has a protein that corrects abnormalities in lipid metabolism.

The response of elderly veterans to daily vitamin D3 supplementation of 2,000 IU: a pilot efficacy study.

OBJECTIVES: To determine the prevalence of hypovitaminosis D (serum 25-hydroxyvitamin D<32 ng/mL; HVD) in a population of elderly veterans and conduct a preliminary assessment of the efficacy of supplementation with cholecalciferol in correcting HVD. DESIGN: Randomized, double-blind, placebo-controlled clinical trial. SETTING: Geriatric clinic at the Bruce W. Carter Veterans Affairs Medical Center, Miami, Florida. PARTICIPANTS: Veterans aged 70 and older. INTERVENTION: Oral cholecalciferol 2,000 IU daily or placebo for 6 months. MEASUREMENTS: Serum calcium, 25-hydroxyvitamin D, parathyroid hormone, and 24-hour urinary calcium. RESULTS: Of the 34 participants who completed the study, 62% had HVD at baseline. In the treatment group, mean serum 25-hydroxyvitamin D level rose from 28.4±7.9 ng/mL at baseline to 42.7±10.5 ng/mL at the end of the trial, but levels remained less than 32 ng/mL in three of 17 (18%) of the participants. In the placebo group, the baseline level of 27.7±8.3 ng/mL remained unchanged (28.8±8.7 ng/mL). Supplementation did not alter serum or urinary calcium levels and did not result in any adverse events. CONCLUSION: These initial observations suggest that, in older veterans, cholecalciferol 2,000 IU daily for 6 months is generally safe and corrects HVD in most but not all individuals.

Not just fun and games: applications of virtual reality in the identification and rehabilitation of cognitive disorders of the elderly.

PURPOSE: To outline the evidence in the published medical literature suggesting the potential applications of virtual reality (VR) for the identification and rehabilitation of cognitive disorders of the elderly. METHOD: Non-systematic literature review. RESULTS: VR, despite its more common usage by younger persons, is a potentially promising source of techniques useful in the identification and rehabilitation of cognitive disorders of the elderly. Systems employing VR can include desktop and head-mounted visual displays among other devices. Thus far, published studies have described VR-based applications in the identification and treatment of deficits in navigational skills in ambulation and driving. In addition, VR has been utilised to enhance the ability to perform activities of daily living in patients with dementia, stroke, and Parkinson's Disease. Such investigations have thus far been small, and unblinded. CONCLUSIONS: VR-based applications can potentially offer more versatile, comprehensive, and safer assessments of function. However, they also might be more expensive, complex and more difficult to use by elderly patients. Side effects of head-mounted visual displays include nausea and disorientation, but, have not been reported specifically in older subjects.

The potential influence of plant polyphenols on the aging process.

Cellular senescence is characterized by cellular hypertrophy: cell growth in the absence of cell division. The genes that regulate this process can be activated or inactivated by numerous plant polyphenols such as resveratrol, quercetin, butein, fistein, piceatannol, curcumin. Many of these substances have been shown to lengthen the lifespan of invertebrates. Many of these compounds have other potential beneficial effects on lifespan as antiatherogenic or antineoplastic agents. Challenges to human testing of such substances on lifespan include determination of dosage, low bioavailability, time and resources necessary to conduct tests, and understanding which formulation of substances to use.

Bugs as drugs, Part 1: Insects: the "new" alternative medicine for the 21st century?

Insects and insect-derived products have been widely used in folk healing in many parts of the world since ancient times. Promising treatments have at least preliminarily been studied experimentally. Maggots and honey have been used to heal chronic and post-surgical wounds and have been shown to be comparable to conventional dressings in numerous settings. Honey has also been applied to treat burns. Honey has been combined with beeswax in the care of several dermatologic disorders, including psoriasis, atopic dermatitis, tinea, pityriasis versicolor, and diaper dermatitis. Royal jelly has been used to treat postmenopausal symptoms. Bee and ant venom have reduced the number of swollen joints in patients with rheumatoid arthritis. Propolis, a hive sealant made by bees, has been utilized to cure aphthous stomatitis. Cantharidin, a derivative of the bodies of blister beetles, has been applied to treat warts and molluscum contagiosum. Combining insects with conventional treatments may provide further benefit.

Obstructive sleep apnea, metabolic syndrome, and age: will geriatricians be caught asleep on the job?

Obstructive sleep apnea (OSA) is increasingly recognized in older persons as an important cause of morbidity and mortality, resulting in cardiovascular disease, cognitive dysfunction, and disturbed sleep. It has been cited as an independent risk factor for the metabolic syndrome (MS). The elevated levels of cytokines, such as interleukin-6 and tumor necrosis factor-alpha, which also increase with age, are a common feature of both OSA and MS. Intermittent hypoxia caused by the recurring episodes of apnea and near-apnea in OSA is a major cause of its systemic effects. Mathematical models of OSA show how obesity and anatomic changes in the upper airways, which may be age-related, interact with the networks responsible for the chemical and neural control of breathing to cause the recurrent intermittent hypoxia of sleep apnea. Treatment of OSA with continuous positive airway pressure improves some aspects of the metabolic syndrome, reduces cardiovascular morbidity, and improves domains of cognitive function. OSA is more difficult to identify in the elderly because many of its symptoms can be caused by other disorders which are common in the elderly. Clinicians who encounter OSA may be advised to search for the presence of MS, and vice versa.

Would the elderly be better off if they were given more placebos?

Placebos are useful in the medical care of the elderly, although the exact definition of a "placebo" or "placebo effect" is difficult to define precisely. They have an important role as control treatments in research trials, but a non-specific "placebo effect" may also be beneficial part of many physician-patient interactions. Physicians also give them deliberately according to several studies worldwide to satisfy patient demands or because they believe in a "placebo effect" among other reasons. A significant placebo effect has been observed among older patients in clinical trials of antidepressants (12-15%), and in treatments of Parkinson's disease (16%). Placebos activate serotonergic pathways in the brain used by antidepressants. In Parkinson's disease, the administration of a placebo stimulates dopamine release in the dorsal (resulting in motor effects) and ventral striatum (which influences expectation of reward). Much of our understanding of the placebo effect comes from studies of placebo analgesia which is influenced by conditioning, expectation, meaning and context of the treatment for the patient, and patient-physician interaction. It is anatomically medicated by brain opioid pathways. Response to "sham" acupuncture in osteoarthritis may be an example of its use in the elderly. Placebos have often been considered a deception and thus unethical. On the other hand, some physicians and ethicists have suggested conditions for appropriate uses for placebos. A placebo might offer the theoretical advantage of an inexpensive treatment that would not cause adverse drug reactions or interactions with other medications, potentially avoiding complications of polypharmacy.

Some new food for thought: the role of vitamin D in the mental health of older adults.

Vitamin D, a multipurpose steroid hormone vital to health, has been increasingly implicated in the pathology of cognition and mental illness. Hypovitaminosis D is prevalent among older adults, and several studies suggest an association between hypovitaminosis D and basic and executive cognitive functions, depression, bipolar disorder, and schizophrenia. Vitamin D activates receptors on neurons in regions implicated in the regulation of behavior, stimulates neurotrophin release, and protects the brain by buffering antioxidant and anti-inflammatory defenses against vascular injury and improving metabolic and cardiovascular function. Although additional studies are needed to examine the impact of supplementation on cognition and mood disorders, given the known health benefits of vitamin D, we recommend greater supplementation in older adults.