VA Sepulveda Ambulatory Care Center

Transgenic mice overexpressing the 695-amino acid isoform of human Alzheimer beta-amyloid (Abeta) precursor protein containing a Lys670 --> Asn, Met671 --> Leu mutation had normal learning and memory in spatial reference and alternation tasks at 3 months of age but showed impairment by 9 to 10 months of age. A fivefold increase in Abeta(1-40) and a 14-fold increase in Abeta(1-42/43) accompanied the appearance of these behavioral deficits. Numerous Abeta plaques that stained with Congo red dye were present in cortical and limbic structures of mice with elevated amounts of Abeta. The correlative appearance of behavioral, biochemical, and pathological abnormalities reminiscent of Alzheimer's disease in these transgenic mice suggests new opportunities for exploring the pathophysiology and neurobiology of this disease.

Falls are a common and often devastating problem among older people, causing a tremendous amount of morbidity, mortality and use of health care services including premature nursing home admissions. Most of these falls are associated with one or more identifiable risk factors (e.g. weakness, unsteady gait, confusion and certain medications), and research has shown that attention to these risk factors can significantly reduce rates of falling. Considerable evidence now documents that the most effective (and cost-effective) fall reduction programmes have involved systematic fall risk assessment and targeted interventions, exercise programmes and environmental-inspection and hazard-reduction programmes. These findings have been substantiated by careful meta-analysis of large numbers of controlled clinical trials and by consensus panels of experts who have developed evidence-based practice guidelines for fall prevention and management. Medical assessment of fall risks and provision of appropriate interventions are challenging because of the complex nature of falls. Optimal approaches involve interdisciplinary collaboration in assessment and interventions, particularly exercise, attention to co-existing medical conditions and environmental inspection and hazard abatement.

BACKGROUND: The Mini-Nutritional Assessment (MNA) is a validated assessment instrument for nutritional problems, but its length limits its usefulness for screening. We sought to develop a screening version of this instrument, the MNA-SF, that retains good diagnostic accuracy. METHODS: We reanalyzed data from France that were used to develop the original MNA and combined these with data collected in Spain and New MEXICO: Of the 881 subjects with complete MNA data, 151 were from France, 400 were from Spain, and 330 were from New MEXICO: Independent ratings of clinical nutritional status were available for 142 of the French subjects. Overall, 73.8% were community dwelling, and mean age was 76.4 years. Items were chosen for the MNA-SF on the basis of item correlation with the total MNA score and with clinical nutritional status, internal consistency, reliability, completeness, and ease of administration. RESULTS: After testing multiple versions, we identified an optimal six-item MNA-SF total score ranging from 0 to 14. The cut-point score for MNA-SF was calculated using clinical nutritional status as the gold standard (n = 142) and using the total MNA score (n = 881). The MNA-SF was strongly correlated with the total MNA score (r = .945). Using an MNA-SF score of > or = 11 as normal, sensitivity was 97.9%, specificity was 100%, and diagnostic accuracy was 98.7% for predicting undernutrition. CONCLUSIONS: The MNA-SF can identify persons with undernutrition and can be used in a two-step screening process in which persons, identified as "at risk" on the MNA-SF, would receive additional assessment to confirm the diagnosis and plan interventions.

OBJECTIVE: To assess the relative effectiveness of interventions to prevent falls in older adults to either a usual care group or control group. DESIGN: Systematic review and meta-analyses. DATA SOURCES: Medline, HealthSTAR, Embase, the Cochrane Library, other health related databases, and the reference lists from review articles and systematic reviews. DATA EXTRACTION: Components of falls intervention: multifactorial falls risk assessment with management programme, exercise, environmental modifications, or education. RESULTS: 40 trials were identified. A random effects analysis combining trials with risk ratio data showed a reduction in the risk of falling (risk ratio 0.88, 95% confidence interval 0.82 to 0.95), whereas combining trials with incidence rate data showed a reduction in the monthly rate of falling (incidence rate ratio 0.80, 0.72 to 0.88). The effect of individual components was assessed by meta-regression. A multifactorial falls risk assessment and management programme was the most effective component on risk of falling (0.82, 0.72 to 0.94, number needed to treat 11) and monthly fall rate (0.63, 0.49 to 0.83; 11.8 fewer falls in treatment group per 100 patients per month). Exercise interventions also had a beneficial effect on the risk of falling (0.86, 0.75 to 0.99, number needed to treat 16) and monthly fall rate (0.86, 0.73 to 1.01; 2.7). CONCLUSIONS: Interventions to prevent falls in older adults are effective in reducing both the risk of falling and the monthly rate of falling. The most effective intervention was a multifactorial falls risk assessment and management programme. Exercise programmes were also effective in reducing the risk of falling.

Though unnecessary for life itself, androgens are essential for the propagation of the species and for establishment and maintenance of the quality of life of males through their support of sexual behavior and function, muscle strength, and sense of well-being. In carrying out its many functions, T acts both as hormone and prohormone. It is an outstanding example of the diverse evolutionary utilization of a primitive informational molecule both among and within species. Not only does T act through the androgen receptor both unchanged and via 5 alpha-reduction, but it acts in tissues with a high aromatase level as an estrogen via the estrogen receptor. Furthermore, DHT, binding to the estrogen receptor, can act as an inhibitor of estrogen action. The products of androgen metabolism may also play active regulatory roles in hematopoiesis and in the regulation of certain hepatic enzymes. Table 3 summarizes the actions of secreted T in males indicating the probable effector hormone. While gross hypogonadism is uncommon, mild androgen insufficiency may be much more frequent, especially in older men, and in those receiving treatment for chronic medical conditions. It is quite possible that such individuals would benefit from appropriate androgen therapy were it available, but the current forms of replacement therapy are not very satisfactory. Better approaches are required. With the exception of a small number of secreted proteins, the products of transcription induced by androgens are not, as yet, known. When the androgen receptor gene is cloned it will be possible to identify androgen-regulated genes and their products. It will then be possible to design agents selectively producing specific desired androgenic effects.

OBJECTIVE: To test the hypothesis that one-leg balance is a significant predictor of falls and injurious falls. DESIGN: Analysis of data from a longitudinal cohort study. SUBJECTS: Healthy, community-living volunteers older than age 60 enrolled in the Albuquerque Falls Study and followed for 3 years (N = 316; mean age 73 years). MAIN OUTCOME MEASURES: Falls and injurious falls detected via reports every other month. INDEPENDENT VARIABLES: Baseline measures of demographics, history, physical examination, Iowa Self Assessment Inventory, balance and gait assessment, and one-leg balance (ability to stand unassisted for 5 seconds on one leg). RESULTS: At baseline, 84.5% of subjects could perform one-leg balance. (Impairment was associated with older age and gait abnormalities.) Over the 3-year follow-up, 71% experienced a fall and 22% an injurious fall. The only independent significant predictor of all falls using logistic regression was age greater than 73. However, impaired one-leg balance was the only significant independent predictor of injurious falls (relative risk: 2.13; 95% CI: 1.04, 4.34; P = .03). CONCLUSION: One-leg balance appears to be a significant and easy-to-administer predictor of injurious falls, but not of all falls. In our study, it was the strongest individual predictor. However, no single factor seems to be accurate enough to be relied on as a sole predictor of fall risk or fall injury risk because so many diverse factors are involved in falling.

OBJECTIVE: To develop and test the effectiveness of a 5-item version of the Geriatric Depression Scale (GDS) in screening for depression in a frail community-dwelling older population. DESIGN: A cross-sectional study. SETTING: A geriatric outpatient clinic at the Sepulveda VA Medical Center, Sepulveda, California. PARTICIPANTS: A total of 74 frail outpatients (98.6% male, mean age 74.6) enrolled in an ongoing trial. MEASUREMENTS: Subjects had a comprehensive geriatric assessment that included a structured clinical evaluation for depression with geropsychiatric consultation. A 5-item version of the GDS was created from the 15-item GDS by selecting the items with the highest Pearson chi2 correlation with clinical diagnosis of depression. Sensitivity, specificity, diagnostic accuracy, and positive and negative predictive values were calculated for the 15-item GDS and the new 5-item scale. RESULTS: Subjects had a mean GDS score of 6.2 (range 0-15). Clinical evaluation found that 46% of subjects were depressed. The depressed and not depressed groups were similar with regard to demographics, mental status, educational level, and number of chronic medical conditions. Using clinical evaluation as the gold standard for depression, the 5-item GDS (compared with the 15-item GDS results shown in parentheses) had a sensitivity of .97 (.94), specificity of .85 (.83), positive predictive value of .85 (.82), negative predictive value of .97 (.94), and accuracy of .90 (.88) for predicting depression. Significant agreement was found between depression diagnosis and the 5-item GDS (kappa = 0.81). Multiple other short forms were tested, and are discussed. The mean administration times for the 5- and 15-item GDS were .9 and 2.7 minutes, respectively. CONCLUSIONS: The 5-item GDS was as effective as the 15-item GDS for depression screening in this population, with a marked reduction in administration time. If validated elsewhere, it may prove to be a preferred screening test for depression.

OBJECTIVE: To review the epidemiology and causes of falls and fall-related injuries in nursing homes and to provide clinicians with a structured framework to evaluate and treat nursing home residents at risk for falls. DATA SOURCES: All large-scale published studies documenting incidence, causes, risk factors, and preventive strategies for falls in nursing homes were reviewed. RESULTS: The mean incidence of falls in nursing homes is 1.5 falls per bed per year (range, 0.2 to 3.6 falls). The most common precipitating causes include gait and balance disorders, weakness, dizziness, environmental hazards, confusion, visual impairment, and postural hypotension. The most important underlying risk factors for falls and injuries include some of these same items and others, such as lower-extremity weakness, gait and balance instability, poor vision, cognitive and functional impairment, and sedating and psychoactive medications. Many strategies for the prevention of falls have been tried, with mixed success. The most successful consider the multifactorial causes of falls and include interventions to improve strength and functional status, reduce environmental hazards, and allow staff to identify and monitor high-risk residents. Strategies that reduce mobility through use of restraints have been shown to be more harmful than beneficial and should be avoided. CONCLUSIONS: A focused history and physical examination after a fall can usually determine both the immediate underlying causes of the fall and contributing risk factors. In addition, regular evaluations in the nursing home can help identify patients at high risk who can then be targeted for specific treatment and prevention strategies.

BACKGROUND: Plasma uric acid has been associated with hypertension in a variety of disorders, and has been shown to be predictive of hypertension. The mechanistic role of uric acid in the development of hypertension is not known however. METHOD: We tested the hypothesis that uric acid stimulates vascular smooth muscle cell (VSMC) proliferation and oxidative stress by stimulating the vascular renin-angiotensin system (RAS). Rat VSMC were exposed to 0-300 micromol uric acid for 48 h. RESULTS: Uric acid (200 and 300 micromol) stimulated the proliferation of VSMC as measured by thymidine uptake. This effect was prevented by 10(-6) mol losartan or by 10(-6) mol captopril. Incubation of VSMC with uric acid for 48 h also increased angiotensinogen messenger RNA expression and intracellular concentrations of angiotensin II. These responses were also inhibited by losartan and captopril. Increased expression of angiotensinogen mRNA was also inhibited by co-incubation with PD 98059, a mitogen-activated protein (MAP) kinase inhibitor. Uric acid stimulated the production of hydrogen peroxide and 8-isoprostane in VSMC. These increases in oxidative stress indicators were significantly reduced by co-incubating the cells with captopril or losartan. Uric acid also decreased nitrite and nitrate concentrations in the culture medium, an effect that was prevented by losartan and captopril. CONCLUSION: These results demonstrate that uric acid stimulates proliferation, angiotensin II production, and oxidative stress in VSMC through tissue RAS. This suggests that uric acid causes cardiovascular disorders by stimulating the vascular RAS, and this stimulation may be mediated by the MAP kinase pathway.

Actigraphy is a method used to study sleep-wake patterns and circadian rhythms by assessing movement, most commonly of the wrist. These evidence-based practice parameters are an update to the Practice Parameters for the Use of Actigraphy in the Clinical Assessment of Sleep Disorders, published in 1995. These practice parameters were developed by the Standards of Practice Committee and reviewed and approved by the Board of Directors of the American Academy of Sleep Medicine. Recommendations are based on the accompanying comprehensive review of the medical literature regarding the role of actigraphy, which was developed by a task force commissioned by the American Academy of Sleep Medicine. The following recommendations serve as a guide to the appropriate use of actigraphy. Actigraphy is reliable and valid for detecting sleep in normal, healthy populations, but less reliable for detecting disturbed sleep. Although actigraphy is not indicated for the routine diagnosis, assessment, or management of any of the sleep disorders, it may serve as a useful adjunct to routine clinical evaluation of insomnia, circadian-rhythm disorders, and excessive sleepiness, and may be helpful in the assessment of specific aspects of some disorders, such as insomnia and restless legs syndrome/periodic limb movement disorder. The assessment of daytime sleepiness, the demonstration of multiday human-rest activity patterns, and the estimation of sleep-wake patterns are potential uses of actigraphy in clinical situations where other techniques cannot provide similar information (e.g., psychiatric ward patients). Superiority of actigraphy placement on different parts of the body is not currently established. Actigraphy may be useful in characterizing and monitoring circadian rhythm patterns or disturbances in certain special populations (e.g., children, demented individuals), and appears useful as an outcome measure in certain applications and populations. Although actigraphy may be a useful adjunct to portable sleep apnea testing, the use of actigraphy alone in the detection of sleep apnea is not currently established. Specific technical recommendations are discussed, such as using concomitant completion of a sleep log for artifact rejection and timing of lights out and on; conducting actigraphy studies for a minimum of three consecutive 24-hour periods; requiring raw data inspection; permitting some preprocessing of movement counts; stating that epoch lengths up to 1 minute are usually sufficient, except for circadian rhythm assessment; requiring interpretation to be performed manually by visual inspection; and allowing automatic scoring in addition to manual scoring methods.

Comprehensive geriatric assessment is a technique for multidimensional diagnosis of frail elderly people with the purpose of planning and/or delivering medical, psychosocial, and rehabilitative care. When comprehensive geriatric assessment is coupled with some therapy, then the term geriatric evaluation and management (GEM) will be used. Following a brief history of comprehensive geriatric assessment, we describe the varied patterns of GEM program organization and review the literature of studies examining GEM effectiveness. Program diversity complicates drawing firm conclusions about GEM effects; however, the vast majority of studies report positive, if not uniformly significant, results. Our analysis suggests that much of the variability in findings is due to sample size limitations. In order to reach conclusions of program effects across studies and to avoid problems of small sample sizes, we undertook a formal meta-analysis. In this initial meta-analysis, we sought to evaluate the effect of GEM programs on a single outcome: mortality. We pooled all published GEM controlled trials into four major groups: inpatient consultation services, inpatient GEM units, home assessment services, and outpatient GEM programs. Meta-analysis of 6-month mortality demonstrates a 39% reduction of mortality for inpatient consultation services (odds ratio 0.61, 95% confidence interval 0.46-0.81, P = 0.0008) and a 37% reduction of mortality for inpatient GEM units (odds ratio 0.63, 95% CI 0.42-0.93, P = 0.02). Home assessment services reduced mortality by 29% (odds ratio 0.71, 95% CI 0.55-0.90, P = 0.005). On the other hand, no significant survival effect was found for outpatient GEM programs (odds ratio 0.96, 95% confidence interval 0.61-1.49).(ABSTRACT TRUNCATED AT 250 WORDS)

Microglial activation is central to the inflammatory response in Alzheimer's Disease (AD). A recently described mouse line, Tg(HuAPP695.K670N/M671L)2576, expressing human amyloid precursor protein with a familial AD gene mutation, age-related amyloid deposits, and memory deficits, was found to develop a significant microglial response using Griffonia simplicifolia lectin or phosphotyrosine probe to identify microglia Both Griffonia simplicifolia lectin and phosphotyrosine staining showed increased numbers of intensely labeled, often enlarged microglia clustered in and around plaques, consistent with microglial activation related to beta-amyloid formation. Using quantitative image analysis of coronal phosphotyrosine-immunostained sections, transgene-positive 10- to 16-month-old, hemizygous, hybrid Tg2576 (APPsw) animals showed significantly increased microglial density and size in plaque-forming areas of hippocampus and frontal, entorhinal, and occipital cortex. Quantitative analysis of microglia as a function of distance from the center of plaques (double labeled for A beta peptide and microglia) revealed highly significant, two- to fivefold elevations in microglial number and area within plaques compared with neighboring regions. Tg2576 beta-amyloid-plaque-forming mice should be a useful system for assessing the consequences of the microglial-mediated inflammatory response to beta-amyloid and developing anti-inflammatory therapeutic strategies for Alzheimer's disease. These results provide the first quantitative link between beta-amyloid plaque formation and microglial activation in an animal model with neuritic plaques and memory deficits.

IN THE last decade, the explosive increase in our knowledge of neuropeptides has demonstrated that the release of peptides from the gastrointestinal tract can modulate behavior; and, contrariwise, gastrointestinal peptides have been shown to be synthesized and released in the central nervous system and act as neurotransmitters. This review will concentrate on the role of peptides as modulators of feeding behavior and weight regulation. The complexities of the neurochemical regulation of food intake are not surprising when one considers the varied inputs involved in the determination of feeding behavior. With depletion of an organism's energy stores, a series of signals arise which force the animal to hunt for food. When the food source is found, the animal needs to do a cost-benefit analysis, i.e. a determination of whether the potential danger and the energy expenditure involved are justified in terms of the calories to be gained and secondarily, to decide whether or not the food is suitable for consumption.

This paper discusses the effects of curcumin on patients with Alzheimer's disease (AD). Curcumin (Turmeric), an ancient Indian herb used in curry powder, has been extensively studied in modern medicine and Indian systems of medicine for the treatment of various medical conditions, including cystic fibrosis, haemorrhoids, gastric ulcer, colon cancer, breast cancer, atherosclerosis, liver diseases and arthritis. It has been used in various types of treatments for dementia and traumatic brain injury. Curcumin also has a potential role in the prevention and treatment of AD. Curcumin as an antioxidant, anti-inflammatory and lipophilic action improves the cognitive functions in patients with AD. A growing body of evidence indicates that oxidative stress, free radicals, beta amyloid, cerebral deregulation caused by bio-metal toxicity and abnormal inflammatory reactions contribute to the key event in Alzheimer's disease pathology. Due to various effects of curcumin, such as decreased Beta-amyloid plaques, delayed degradation of neurons, metal-chelation, anti-inflammatory, antioxidant and decreased microglia formation, the overall memory in patients with AD has improved. This paper reviews the various mechanisms of actions of curcumin in AD and pathology.

BACKGROUND: The benefits of intravenous tissue-type plasminogen activator (tPA) in acute ischemic stroke are time dependent, and guidelines recommend an arrival to treatment initiation (door-to-needle) time of ≤60 minutes. METHODS AND RESULTS: Data from acute ischemic stroke patients treated with tPA within 3 hours of symptom onset in 1082 hospitals participating in the Get With the Guidelines-Stroke Program from April 1, 2003, to September 30, 2009 were studied to determine frequency, patient and hospital characteristics, and temporal trends in patients treated with door-to-needle times ≤60 minutes. Among 25 504 ischemic stroke patients treated with tPA, door-to-needle time was ≤60 minutes in only 6790 (26.6%). Patient factors most strongly associated with door-to-needle time ≤60 minutes were younger age, male gender, white race, or no prior stroke. Hospital factors associated with ≤60 minute door-to-needle time included greater annual volumes of tPA-treated stroke patients. The proportion of patients with door-to-needle times ≤60 minutes varied widely by hospital (0% to 79.2%) and increased from 19.5% in 2003 to 29.1% in 2009 (P<0.0001). Despite similar stroke severity, in-hospital mortality was lower (adjusted odds ratio, 0.78; 95% confidence interval, 0.69 to 0.90; P<0.0003) and symptomatic intracranial hemorrhage was less frequent (4.7% versus 5.6%; P<0.0017) for patients with door-to-needle times ≤60 minutes compared with patients with door-to-needle times >60 minutes. CONCLUSIONS: Fewer than one-third of patients treated with intravenous tPA had door-to-needle times ≤60 minutes, with only modest improvement over the past 6.5 years. These findings support the need for a targeted initiative to improve the timeliness of reperfusion in acute ischemic stroke.

Alzheimer's disease (AD) can be diagnosed with a considerable degree of accuracy. In some centers, clinical diagnosis predicts the autopsy diagnosis with 90% certainty in series reported from academic centers. The characteristic histopathologic changes at autopsy include neurofibrillary tangles, neuritic plaques, neuronal loss, and amyloid angiopathy. Mutations on chromosomes 21, 14, and 1 cause familial AD. Risk factors for AD include advanced age, lower intelligence, small head size, and history of head trauma; female gender may confer additional risks. Susceptibility genes do not cause the disease by themselves but, in combination with other genes or epigenetic factors, modulate the age of onset and increase the probability of developing AD. Among several putative susceptibility genes (on chromosomes 19, 12, and 6), the role of apolipoprotein E (ApoE) on chromosome 19 has been repeatedly confirmed. Protective factors include ApoE-2 genotype, history of estrogen replacement therapy in postmenopausal women, higher educational level, and history of use of nonsteroidal anti-inflammatory agents. The most proximal brain events associated with the clinical expression of dementia are progressive neuronal dysfunction and loss of neurons in specific regions of the brain. Although the cascade of antecedent events leading to the final common path of neurodegeneration must be determined in greater detail, the accumulation of stable amyloid is increasingly widely accepted as a central pathogenetic event. All mutations known to cause AD increase the production of beta-amyloid peptide. This protein is derived from amyloid precursor protein and, when aggregated in a beta-pleated sheet configuration, is neurotoxic and forms the core of neuritic plaques. Nerve cell loss in selected nuclei leads to neurochemical deficiencies, and the combination of neuronal loss and neurotransmitter deficits leads to the appearance of the dementia syndrome. The destructive aspects include neurochemical deficits that disrupt cell-to-cell communications, abnormal synthesis and accumulation of cytoskeletal proteins (e.g., tau), loss of synapses, pruning of dendrites, damage through oxidative metabolism, and cell death. The concepts of cognitive reserve and symptom thresholds may explain the effects of education, intelligence, and brain size on the occurrence and timing of AD symptoms. Advances in understanding the pathogenetic cascade of events that characterize AD provide a framework for early detection and therapeutic interventions, including transmitter replacement therapies, antioxidants, anti-inflammatory agents, estrogens, nerve growth factor, and drugs that prevent amyloid formation in the brain.

It has been reported that hypertension and obesity often coexist with hyperuricemia. To clarify the relations between serum uric acid, plasma norepinephrine, and insulin or leptin levels in subjects with weight gain-induced blood pressure elevation, we conducted the present longitudinal study. In 433 young, nonobese, normotensive men, body mass index, blood pressure, and levels of serum uric acid, fasting plasma norepinephrine, insulin, and leptin were measured every year for 5 years. Subjects were stratified by significant weight gain and/or blood pressure elevation (>10% in body mass index or mean blood pressure) for 5 years. At entry, blood pressure, uric acid, and norepinephrine values in subjects with blood pressure elevation were greater than in those without it, although body mass index, insulin, and leptin were similar. At entry, body mass index, blood pressure, uric acid, and norepinephrine in subjects with weight gain were greater than in those without weight gain. The increases in body mass index, mean blood pressure, uric acid, norepinephrine, insulin, and leptin for 5 years were greater in subjects with blood pressure elevation and/or weight gain than in subjects without, and those increases were greatest in subjects with weight gain whose blood pressure was elevated. By multiple regression analysis, basal mean blood pressure, norepinephrine, and uric acid were significant determinant factors of changes in mean blood pressure over 5 years, and basal body mass index, norepinephrine, and uric acid were significant determinant factors of changes in body mass index. These results demonstrate that serum uric acid and plasma norepinephrine concentrations predict subsequent weight gain and blood pressure elevation.

BACKGROUND: Transdermal nicotine therapy is widely used to aid smoking cessation, but there is uncertainty about its safety in patients with cardiac disease. METHODS: In a randomized, double-blind, placebo-controlled trial at 10 Veterans Affairs medical centers, we randomly assigned 584 outpatients (of whom 576 were men) with at least one diagnosis of cardiovascular disease to a 10-week course of transdermal nicotine or placebo as an aid to smoking cessation. The subjects were monitored for a total of 14 weeks for the primary end points of the study (death, myocardial infarction, cardiac arrest, and admission to the hospital due to increased severity of angina, arrhythmia, or congestive heart failure); the secondary end points (admission to the hospital for other reasons and outpatient visits necessitated by increased severity of heart disease); any side effects of therapy; and abstinence from smoking. RESULTS: There were 48 primary and 78 secondary end points noted in a total of 95 subjects. At least one of the primary end points was reached by 5.4 percent of the subjects in the nicotine group and 7.9 percent of the subjects in the placebo group (difference, 2.5 percent; 95 percent confidence interval, -1.6 to 6.5 percent; P=0.23). In the nicotine group, 11.9 percent of the subjects had at least one of the secondary end points, as compared with 9.7 percent in the placebo group (difference, 2.2 percent; 95 percent confidence interval, -2.2 to 7.4 percent; P= 0.37). After 14 weeks the rate of abstinence from smoking was 21 percent in the nicotine group, as compared with 9 percent in the placebo group (P=0.001), but after 24 weeks the abstinence rates were not significantly different (14 percent vs. 11 percent, P= 0.67). CONCLUSIONS: Transdermal nicotine does not cause a significant increase in cardiovascular events in high-risk outpatients with cardiac disease. However, the efficacy of transdermal nicotine as an aid to smoking cessation in such patients is limited and may not be sustained over time.

Human status epilepticus (SE) is consistently associated with cognitive problems, and with widespread neuronal necrosis in hippocampus and other brain regions. In animal models, convulsive SE causes extensive neuronal necrosis. Nonconvulsive SE in adult animals also leads to widespread neuronal necrosis in vulnerable regions, although lesions develop more slowly than they would in the presence of convulsions or anoxia. In very young rats, nonconvulsive normoxic SE spares hippocampal pyramidal cells, but other types of neurons may not show the same resistance, and inhibition of brain growth, DNA and protein synthesis, and of myelin formation and of synaptogenesis may lead to altered brain development. Lesions induced by SE may be epileptogenic by leading to misdirected regeneration. In SE, glutamate, aspartate, and acetylcholine play major roles as excitatory neurotransmitters, and GABA is the dominant inhibitory neurotransmitter. GABA metabolism in substantia nigra (SN) plays a key role in seizure arrest. When seizures stop, a major increase in GABA synthesis is seen in SN postictally. GABA synthesis in SN may fail in SE. Extrasynaptic factors may also play an important role in seizure spread and in maintaining SE. Glial immaturity, increased electronic coupling, and SN immaturity facilitate SE development in the immature brain. Major increases in cerebral blood flow (CBF) protect the brain in early SE, but CBF falls in late SE as blood pressure falters. At the same time, large increases in cerebral metabolic rate for glucose and oxygen continue throughout SE. Adenosine triphosphate (ATP) depletion and lactate accumulation are associated with hypermetabolic neuronal necrosis. Excitotoxic mechanisms mediated by both N-methyl-D-aspartate (NMDA) and non-NMDA glutamate receptors open ionic channels permeable to calcium and play a major role in neuronal injury from SE. Hypoxia, systemic lactic acidosis, CO2 narcosis, hyperkalemia, hypoglycemia, shock, cardiac arrhythmias, pulmonary edema, acute renal tubular necrosis, high output failure, aspiration pneumonia, hyperpyrexia, blood leukocytosis and CSF pleocytosis are common and potentially serious complications of SE. Our improved understanding of the pathophysiology of brain damage in SE should lead to further improvement in treatment and outcome.

BACKGROUND AND METHODS: The prevention of disability in elderly people poses a challenge for health care and social services. We conducted a three-year, randomized, controlled trial of the effect of annual in-home comprehensive geriatric assessment and follow-up for people living in the community who were 75 years of age or older. The 215 people in the intervention group were seen at home by gerontologic nurse practitioners who, in collaboration with geriatricians, evaluated problems and risk factors for disability, gave specific recommendations, and provided health education. The 199 people in the control group received their regular medical care. The main outcome measures were the prevention of disability, defined as the need for assistance in performing the basic activities of daily living (bathing, dressing, feeding, grooming, transferring from bed to chair, and moving around inside the house) or the instrumental activities of daily living (e.g., cooking, handling finances and medication, housekeeping, and shopping), and the prevention of nursing home admissions. RESULTS: At three years, 20 people in the intervention group (12 percent of 170 surviving participants) and 32 in the control group (22 percent of 147 surviving participants) required assistance in performing the basic activities of daily living (adjusted odds ratio, 0.4; 95 percent confidence interval, 0.2 to 0.8; P = 0.02). The number of persons who were dependent on assistance in performing the instrumental activities of daily living but not the basic activities did not differ significantly between the two groups. Nine people in the intervention group (4 percent) and 20 in the control group (10 percent) were permanently admitted to nursing homes (P = 0.02). Acute care hospital admissions and short-term nursing home admissions did not differ significantly between the two groups. In the second and third years of the study, there were significantly more visits to physicians among the participants in the intervention group than among those in the control group (mean number of visits per month, 1.41 in year 2 and 1.27 in year 3 in the intervention group, as compared with 1.11 and 0.92 visits, respectively, in the control group; P = 0.007 and P = 0.001, respectively). The cost of the intervention for each year of disability-free life gained was about $46,000. CONCLUSIONS: A program of in-home comprehensive geriatric assessments can delay the development of disability and reduce permanent nursing home stays among elderly people living at home.