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Alloying transition metals, such as Mo, into BiVO4 has emerged as the primary mechanism for improving carrier transport in this photoanode for solar fuels production. The present work establishes the generality of improving photoelectrochemical performance through co-alloying with a transition metal electron donor and a structure-modulating rare earth. Further improvement for all such alloys is obtained by annealing the oxide materials in H2, ultimately producing photoanodes with above 3 mA cm-2 photocurrent density under AM 1.5G illumination, in the top tier of compact BiVO4 films.

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OBJECTIVE: To preliminarily assess the safety and efficacy of transdermal nicotine therapy on cognitive performance and clinical status in subjects with mild cognitive impairment (MCI). METHODS: Nonsmoking subjects with amnestic MCI were randomized to transdermal nicotine (15 mg per day or placebo) for 6 months. Primary outcome variables were attentional improvement assessed with Connors Continuous Performance Test (CPT), clinical improvement as measured by clinical global impression, and safety measures. Secondary measures included computerized cognitive testing and patient and observer ratings. RESULTS: Of 74 subjects enrolled, 39 were randomized to nicotine and 35 to placebo. 67 subjects completed (34 nicotine, 33 placebo). The primary cognitive outcome measure (CPT) showed a significant nicotine-induced improvement. There was no statistically significant effect on clinician-rated global improvement. The secondary outcome measures showed significant nicotine-associated improvements in attention, memory, and psychomotor speed, and improvements were seen in patient/informant ratings of cognitive impairment. Safety and tolerability for transdermal nicotine were excellent. CONCLUSION: This study demonstrated that transdermal nicotine can be safely administered to nonsmoking subjects with MCI over 6 months with improvement in primary and secondary cognitive measures of attention, memory, and mental processing, but not in ratings of clinician-rated global impression. We conclude that this initial study provides evidence for nicotine-induced cognitive improvement in subjects with MCI; however, whether these effects are clinically important will require larger studies. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that 6 months of transdermal nicotine (15 mg/day) improves cognitive test performance, but not clinical global impression of change, in nonsmoking subjects with amnestic MCI.

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OBJECTIVE: To compare the efficacy and tolerability of dehydroepiandrosterone (DHEA) vs placebo in AD. METHOD: Fifty-eight subjects with AD were randomized to 6 month's treatment with DHEA (50 mg per os twice a day; n = 28) or placebo (n = 30) in a multi-site, double-blind pilot trial. Primary efficacy measures assessed cognitive functioning (the AD Assessment Scale-Cognitive [ADAS-Cog]) and observer-based ratings of overall changes in severity (the Clinician's Interview-Based Impression of Change with Caregiver Input [CIBIC-Plus]). At baseline, 3 months, and 6 months, the ADAS-Cog was administered, and at 3 and 6 months, the CIBIC-Plus was administered. The 6-month time point was the primary endpoint. RESULTS: Nineteen DHEA-treated subjects and 14 placebo-treated subjects completed the trial. DHEA was relatively well-tolerated. DHEA treatment, relative to placebo, was not associated with improvement in ADAS-Cog scores at month 6 (last observation carried forward; p = 0.10); transient improvement was noted at month 3 (p = 0.014; cutoff for Bonferroni significance = 0.0125). No difference between treatments was seen on the CIBIC-Plus at either the 6-month or the 3-month time points. CONCLUSIONS: DHEA did not significantly improve cognitive performance or overall ratings of change in severity in this small-scale pilot study. A transient effect on cognitive performance may have been seen at month 3, but narrowly missed significance.

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BACKGROUND: There has been a paucity of well-designed studies comparing selective serotonin reuptake inhibitor (SSRI) medications in the treatment of depression in the elderly. This multicenter study was designed to examine the efficacy and safety of sertraline and fluoxetine in depressed elderly outpatients. A secondary objective was to examine the effects of SSRI treatment on quality of life and cognitive function. METHOD: Two hundred thirty-six outpatients 60 years of age and older who met DSM-III-R criteria for major depressive disorder received 1 week of single-blind placebo before being randomly assigned to 12 weeks of double-blind, parallel-group treatment with flexible daily doses of either sertraline (range, 50-100 mg) or fluoxetine (range, 20-40 mg). Primary efficacy measures consisted of the 24-item Hamilton Rating Scale for Depression and Clinical Global Impressions scale ratings. Secondary outcome assessments included clinician- and patient-rated measures of depression symptoms and factors, cognitive functioning, and quality of life, as well as plasma drug concentrations, which were correlated with clinical response. RESULTS: Both drugs produced a similarly positive response on the primary efficacy measures, with 12-week responder rates of 73% for sertraline and 71% for fluoxetine. Sertraline-treated patients showed statistically greater cognitive improvement on several measures. Both drugs were safe and well tolerated. CONCLUSION: Data indicate that both drugs are effective antidepressants for the treatment of depressed elderly outpatients. Differences in cognitive performance effects deserve further investigation.

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Nicotinic systems play an important role in the neural basis of working memory and attention. Recent progress in understanding of the structure, function, and distribution of central nervous system (CNS) nicotinic receptors and their pharmacology has opened up new possibilities for novel CNS therapeutics with nicotinic agents. In this paper, we review the theoretical justification and the experimental evidence supporting these developments. We focus on the applications of nicotinic agonists in CNS disorders that are degenerative in nature, namely Parkinson's disease and Alzheimer's disease. We suggest that there is considerable potential for therapeutic applications in the near future. Clinically, two major issues remain: (a) the selectivity of effects, that is, developing compounds which are selective in producing improvement in cognition, motor function, attention, or pain without significant side-effects; and (b) the realistic likelihood of long-term improvements in everyday functioning in people who have degenerative diseases.

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Post-mortem studies have demonstrated a substantial loss of nicotinic receptors in Parkinson's disease (PD), which may be at least partially responsible for some of the cognitive, motoric, and behavioral deficits seen in this disorder. Epidemiologic studies have suggested that cigarette smoking is a strong negative risk factor for the development of PD. We have previously shown that blockade of central nicotinic receptors produces cognitive impairment in areas of new learning, short-term memory, and psychomotor slowing with increasing dose sensitivity with age and disease. Studies of acute stimulation of nicotinic receptors in Alzheimer's disease with nicotine and the novel agonist ABT-418 in our laboratory and others have shown improvements in several measures of cognitive function. Prior studies of the effects of nicotine in PD have suggested some improvements in clinical symptomatology. We have begun quantitative studies of both acute and chronic nicotine in PD to assess both cognitive and motor effects. Fifteen (15) nondemented subjects (age 66 +/- 5.3; M/F = 11/4) with early to moderate PD (mean Hoehn-Yahr stage = 1.77; MMSE = 28.6) received a dose-ranging study of intravenous nicotine up to 1.25 microg/kg/min, followed by chronic administration of nicotine by transdermal patch with doses ranging up to 14 mg per day for 2 weeks. Testing occurred both during drug administration and up to 2 months after drug cessation to look for prolonged effects. Preliminary analysis shows improvements after acute nicotine in several areas of cognitive performance, particularly measures such as reaction time, central processing speed, and decreased tracking error. Improvements in attention and semantic retrieval were not seen. After chronic nicotine, improvements were seen in several motor measures suggesting improved extrapyramidal functioning. This appeared to be sustained for up to 1 month after drug. The treatment was well tolerated. Nicotinic stimulation may have promise for improving both cognitive and motor aspects of Parkinson's disease.

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Advances in the understanding of the structure, function, and distribution of central nervous system (CNS) nicotinic receptors has provided the impetus for new studies examining the role(s) that these receptors and associated processes may play in CNS functions. Further motivation has come from the realization that such receptors are changed in degenerative neurologic diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). Ongoing investigations of the molecular substructure of CNS nicotinic receptors and their pharmacology have begun to open up new possibilities for novel CNS therapeutics with nicotinic agents. Exploiting these possibilities will require understanding of the role(s) that these receptor systems play in human cognitive, behavioral, motor, and sensory functioning. Clues from careful studies of human cognition and behavior are beginning to emerge and will provide direction for studies of potentially therapeutic novel nicotinic agents. Modulation of these receptors with the ultimate goal of producing therapeutic benefits is the goal of these investigations and drug development. This paper will review studies from our laboratory and others that point to the importance of CNS nicotinic mechanisms in normal human cognitive and behavioral functioning as well as their role in disease states. In addition, this paper will examine potential clinical applications of nicotine and/or nicotinic agonists in a variety of CNS disorders with particular emphasis on structural brain disease including: movement disorders such as Parkinson's disease and Tourette's syndrome, cognitive/behavioral disorders such as Alzheimer's disease, attention deficit/hyperactivity disorder, and schizophrenia, and other more speculative applications. Important results from early therapeutic studies of nicotine and/or nicotinic agonists in these disease states are presented. For example, recent studies with nicotine and novel nicotinic agonists such as ABT-418 by our group in AD patients suggest that nicotinic stimulation can improve the acquisition and retention of verbal information and decrease errors. Preliminary results from a series of studies examining the acute and subchronic quantitative effects of nicotine on cognitive and motor functioning in Parkinson's disease suggest that acute nicotine administration and stimulation improves some aspects of cognitive and motor performance and may improve the processing speed of more complex tasks. The most likely near-term applications of novel nicotinic agonists in CNS disorders are likely to be in those disorders that are degenerative in nature, e.g. Parkinson's disease and Alzheimer's disease, or other movement disorders such as Tourette's syndrome. The most likely direct therapeutic role for nicotinic agonists is as augmentation therapy in combination with other agents rather than as monotherapy, except early in disease states or as a prophylactic or preventative treatment.

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BACKGROUND: The efficacy of extended-release physostigmine salicylate, an acetylcholinesterase inhibitor, was evaluated in 850 subjects with mild-to-moderate Alzheimer disease (AD) in a multicenter trial. METHODS: Subjects initially entered a dose-enrichment phase in which they received 1 week each of physostigmine salicylate, 24 mg/d and 30 mg/d, and daily placebo. Among the subjects who completed this phase, 35.9% responded to physostigmine treatment, whereas 62.4% were considered nonresponders, and 1.6% could not be evaluated because of missing data. After a 4-week placebo-washout phase, 176 responder subjects were randomized to receive their best dose of physostigmine or placebo in a 12-week double-blind phase. Primary efficacy measures included the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog), the Clinician's Interview-Based Impression of Change With Caregiver Input (CIBIC+), and the Clinical Global Impression of Change (CGIC). RESULTS: In the intent-to-treat analysis of the double-blind phase, physostigmine-treated subjects scored -2.02 points better than placebo-treated subjects on the ADAS-Cog (F1,167 = 6.42 [P = .01]) and 0.33 points higher on the CIBIC+ (F1,150 = 5.68 [P = .02]). No significant improvement was observed on the CGIC or the secondary outcome measures. Nausea and vomiting were experienced by 47.0% of all physostigmine-treated subjects during the double-blind phase. CONCLUSIONS: Physostigmine demonstrated a statistically significant benefit compared with placebo on a clinical global rating of change and an objective test of cognitive function. Given the frequency of gastrointestinal side effects, the role of this agent in clinical use remains to be determined.

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To explore further the potential for cognitive enhancement utilizing nicotinic stimulation in Alzheimer's disease (AD), six otherwise healthy subjects with moderate AD received placebo and three doses (6, 12, and 23 mg) of the novel selective cholinergic channel activator (ChCA) (nicotinic agonist) ABT-418 over 6 h in a double-blind, within-subjects, repeated-measures design. Subjects showed significant improvements in total recall and a decline in recall failure on a verbal learning task. Qualitatively similar improvements were seen in non-verbal learning tasks such as spatial learning and memory, and repeated acquisition. No significant behavioral, vital sign, or physical side effects were seen. These results confirm that stimulating central nicotinic receptors has acute cognitive benefit in AD patients. These findings suggest that selective ChCAs have a potential therapeutic role in dementing disorders, and that further studies with this or similar agents in AD and/or Parkinson's disease are warranted.

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Stasis of viscid secretions in cystic fibrosis (CF) leads to chronic infection, inflammation, and lung destruction. Chest physiotherapy (CPT) has been used for many years to assist in the removal of these secretions. However, the need for independently administered CPT exists, particularly for adolescents and the older CF patient. Two devices, the intrapulmonary percussive ventilator (IPV) and the Flutter device (Flutter) have been promoted for this purpose. This study compares these devices to standard, manual CPT. There was no difference in sputum quantity produced with any method studied. Transiently lower oxygen saturation was noted with standard CPT compared with the IPV and Flutter. Inconsistent but significant improvements in flow rates were noted with the two devices compared to standard CPT. Important trends to lower lung volumes, probably indicating decreased air trapping, were also noted with all three therapies at 1 and 4 hours after administration. There were no adverse effects with any treatment regimen. Larger and longer studies of these devices compared to standard CPT and with each other are warranted to assess their value for independent administration of CPT in CF patients and to determine long-term effects on maintenance of pulmonary function.

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Advances in our understanding of the structure, function and distribution of nicotinic acetylcholine receptors in the CNS have provided the impetus for new studies examining the role(s) that these receptors and associated processes may play in CNS functions. Further motivation has come from the realisation that such receptors must be involved in the maintenance of cigarette smoking, and from clues provided by studies of degenerative neurological diseases such as Alzheimer's disease and Parkinson's disease, in which the loss of nicotinic receptors has been described. Ongoing investigations of the molecular substructure of central nicotinic receptors and their pharmacology have begun to open up new possibilities for novel CNS therapeutics with nicotinic agents. Exploiting these possibilities will require understanding of the role(s) that these receptor systems play in human cognitive, behavioural, motor and sensory functioning. Clues from careful studies of human cognition are beginning to emerge and will provide direction for studies of potentially therapeutic novel nicotinic agents. Despite the promising results of acute studies, few long term studies with nicotine or nicotinic drugs have been performed in dementing disorders. Thus there is uncertainty as to whether long term nicotinic treatment will provide sustained cognitive benefit. It is even more uncertain whether such cognitive benefit will have a significant clinical impact on patients and their families. To maximise the potential benefit of long term treatment with nicotinic agonists (or other cholinergic drugs), we suggest that drug treatment should be combined with cognitive rehabilitation strategies. This will enable patients and/or their families to focus on the particular cognitive domains that may be improved.

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Weight loss is common in Alzheimer's disease (AD), but its pathogenesis is poorly understood. It is unclear whether an elevated daily energy expenditure contributes to the weight loss. We tested the hypothesis that daily energy expenditure is higher in AD patients compared to healthy elderly. Thirty AD (73 +/- 8 years; Mini-Mental State Examination score: 16 +/- 8) and 103 healthy elderly (69 +/- 7 years) were characterized for daily energy expenditure and its components (resting and free-living physical activity energy expenditure) from doubly labeled water and indirect calorimetry. Fat-free mass and fat mass were measured from dual energy X-ray absorptiometry. Fat-free mass tended to be lower in AD patients (45 +/- 9 kg) versus healthy elderly (49 +/- 10 kg; p = 0.07), whereas no differences were noted in fat mass between groups. Daily energy expenditure was 14% lower in AD (1901 +/- 517 kcal/d) compared to healthy elderly (2213 +/- 513 kcal/d; p < 0.001), due to lower resting (1287 +/- 227 versus 1418 +/- 246 kcal/d; p < 0.01) and physical activity energy expenditures (425 +/- 317 versus 574 +/- 342 kcal/d; p < 0.05). No differences in energy expenditure were noted between groups after controlling for differences in body composition. Daily energy expenditure was examined in a subgroup (n = 11) of AD patients who lost significant body weight (5.6 +/- 2.3 kg) within the past year. There was a lower daily energy expenditure in cachectic AD patients (1799 +/- 474 kcal/d) versus non-cachectic patients (1960 +/- 544 kcal/d) and healthy elderly (2213 +/- 513 kcal/d; p < 0.01). Similarly, no differences in energy expenditure were noted between groups after controlling for differences in body composition. We conclude that absolute levels of daily energy expenditure are lower in AD patients due to their lower body mass. However, after taking into account differences in body composition, daily energy expenditure in AD patients is appropriate for their metabolic size. The hypothesis that elevated daily energy expenditure contributes to weight loss in AD is not supported by these findings.

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OBJECTIVE: It has previously been suggested that Alzheimer's disease patients have higher resting energy requirements than healthy individuals, which may contribute to their unexplained weight loss. We examined whether resting metabolic rate, the largest component of daily energy expenditure, is elevated in Alzheimer's patients compared with healthy older controls. DESIGN: Cross-sectional. SETTING: General Clinical Research Center and Baltimore VA Medical Center. PATIENTS: Twenty-five noninstitutionalized demented patients (74 +/- 8 years; mean +/- SD) with a wide range of Mini-Mental Examination scores (1 to 20) and 73 healthy older individuals (69 +/- 7 years). MEASUREMENTS: Resting metabolic rate was measured by indirect calorimetry, fat-free mass and fat mass by dual energy X-ray absorptiometry, and daily energy intake by food diaries. RESULTS: No differences in fat-free mass and fat mass were noted between Alzheimer's disease patients and healthy older controls. Resting metabolic rate was similar in Alzheimer's disease patients (5446 +/- 962 kJ/day) and healthy older individuals (5647 +/- 887 kJ/day). These results persisted when resting metabolic rate was statistically adjusted for differences in body composition and age. CONCLUSION: These results provide no evidence for an elevation in resting energy requirements in noninstitutionalized demented patients.

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The treatment of depression can be problematic in the elderly patient. The advent of the serotonin selective reuptake inhibitors (SSRIs) represents a significant advance in the treatment of depression. Sufficient data from controlled studies now exist on the efficacy and safety of these agents in geriatric patients to recommend them as a primary treatment for major depressive disorder. SSRIs appear to have significant advantages over older drugs, especially tricyclic agents, in this age group. The lack of significant anticholinergic and antihistaminergic side effects results in better tolerability and better compliance. While SSRIs are not free of side effects, those that occur can usually be managed in the context of continued treatment of the depressive episode. This article reviews data from controlled studies of the treatment of geriatric depression for all four available SSRIs in the United States-fluoxetine, sertraline, paroxetine, and fluvoxamine (which is approved in the United States for treating only obsessive-compulsive disorder). Differences among the SSRIs are examined, particularly with reference to clinically relevant differences in pharmacokinetics and hepatic isoenzyme inhibition. Principles of clinical management are discussed, including dose initiation and titration, side effect management, augmentation and combinations, and length of treatment. Finally, the use of SSRIs in special elderly populations is discussed.

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The proceedings of the inaugural scientific meeting of the Society for Research on Nicotine and Tobacco (SRNT) are summarized. The primary objective of the meeting was to foster the exchange of information on the effects of nicotine and tobacco use, as well as factors which influence their use, drawing from biological, behavioral and social sciences. Much of this research can be viewed as a tale of "two" drugs--nicotine as a key to an important public health problem, and nicotine as a classical tool of physiological and pharmacological research. A historical overview of research on "both" drugs is provided first. Public policy alternatives for reducing the prevalence of tobacco use have been derived in part from basic and clinical research results and are briefly outlined. Evidence for genetic determinants on nicotine use and effects is presented using data from twin studies and from molecular genetic research with humans and animals. Consistent with this research, there is evidence of individual differences in pharmacokinetics and effects of nicotine, which could account for differences in smoking behavior and nicotine dependence. Finally, recent developments in the therapeutic uses of nicotine and novel nicotinic agonists with schizophrenia, Alzheimer's disease, Parkinson's disease, Tourette's syndrome and ulcerative colitis are presented. Overall, the research presented at the meeting demonstrated the vast diversity of areas of study involving nicotine and tobacco, as well as the rich opportunities for cross-communication among researchers from different disciplines.

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BACKGROUND: We examined the effect of high-dose selegiline in 16 treatment-resistant older depressive patients. We hypothesized that selegiline, at a dosage of 60 mg/d, would be at least partially effective but that the higher doses would not maintain the monoamine oxidase B selectivity observed with the lower doses of selegiline. METHODS: Sixteen treatment-resistant subjects (mean [+/- SD] age, 65.6 +/- 9.3 years) entered a double-blind, randomized, crossover study of placebo vs 3 weeks of selegiline at a dosage of 60 mg/d. Objective measures of mood and behavior were obtained in all subjects, and 10 of the subjects underwent repeated lumbar punctures for analysis of monoamine metabolites in the cerebrospinal fluid. RESULTS: Objective measures of mood and behavior revealed significant improvement in the Hamilton Depression Rating Scale score (37.4% decrease), the Global Depression score (22.7% decrease), and the Brief Psychiatric Rating Scale score (19.3% decrease); subjective behavioral measures, however, did not show significant improvement during the 3-week medication trial. Cerebrospinal fluid values revealed a statistically significant drop in 3-methoxy-4-hydroxyphenylglycol (51%) and 5-hydroxyindoleacetic acid (17%) levels, and there was a significant lowering of systolic blood pressure on standing (15%), but these changes were not accompanied by clinical side effects. CONCLUSIONS: Our results suggest that high-dose selegiline can be an effective antidepressant in treatment-resistant older depressive patients. While the selegiline dose required has nonselective monoamine oxidase effects and thus would not be free of possible tyramine interactions, other advantages suggest that further investigations with selegiline are warranted in this population.

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Studies of the neurochemical pathology of Alzheimer's disease and Parkinson's disease reveal a severe and specific loss of central nicotinic cholinergic receptors. We have investigated the functional significance of this finding for cognitive functioning by studying the effects of the centrally active nicotinic antagonist mecamylamine. Single oral doses of mecamylamine were administered to 12 healthy young males and 15 healthy elderly subjects in doses of 5, 10, and 20 mg in a placebo-controlled, double-blind study. In both groups, the 20-mg dose caused a significant increase in errors in the learning condition of the Repeated Acquisition Task, producing a slower acquisition curve. There was no effect of drug on the performance component (retrieval of previously learned information). However, elderly subjects showed enhanced sensitivity to mecamylamine, with 10-mg dose producing significant impairment of learning not seen in the young normals. On a recognition memory task, there was an age-associated shift in response bias, with the elderly subjects becoming more liberal with increasing dose. Reaction-time measures suggested a dose-related slowing of reaction time on several tasks. Behavioral effects were minimal and physiologic effects were consistent with dose-related ganglionic blockade. These results indicate that acute blockade of nicotinic receptor function can produce measurable and significant cognitive impairment similar to some deficits seen in dementing illnesses, and that there is an age-related increase in sensitivity to nicotinic blockade.

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The purpose of this study was to examine motor memory strategies using sleep deprivation as a probe. Eighteen healthy men participated in a three-day study in which they underwent repeated testing on a kinesthetic arm position replication task. On the morning of Day 3, after approximately 48 hr sleep deprivation, they ingested either 20 mg d-amphetamine or placebo. Results showed that throughout Day 3 performance remained relatively unimpaired at medial positions for both groups. For positions shifted 25 degrees laterally, accuracy was also relatively unimpaired for the amphetamine group but was compromised for the placebo group. It was concluded that sleep deprivation-induced decrements in positioning ability were due to disruption of kinesthetic memory, a narrowing of attention, or both. Kinesthetic feedback, and encoding and retrieval processes of the spatial reference system were preserved.

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To examine the independent contributions of the attentional components of arousal and activation in performance, sleep deprivation was used as the attentional manipulation in a reaction time (RT) task. The subjects were 18 men who underwent 63 hr. of sleep deprivation during which time they periodically performed a simple auditory RT task with manipulations of temporal uncertainty and intensity. After 48 hr. sleep deprivation, subjects ingested either 20 mg d-amphetamine or placebo, then continued testing throughout Day 3. During sleep deprivation, performance was more impaired on trials associated with low temporal uncertainty (arousal) and high preparation (activation) than on trials associated with high temporal uncertainty and low preparation. Analysis indicated that sleep deprivation perturbed activation, leaving arousal relatively unimpaired and that amphetamine had a restorative effect on the sleep deprivation-impaired activation system. The stimulus of high intensity was disruptive on Day 1 but facilitative on Day 3, a result which was interpreted as an initial inhibition, then disinhibition of arousal. Results were interpreted to indicate that, in some instances, alterations in the less specific arousal and activation systems may underlie impairment or changes in the more specific information processing and motor output stages.

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