Radionecrosis and cellular changes in small volume stereotactic brain radiosurgery in a porcine model.

Stereotactic radiosurgery (SRS) has proven an effective tool for the treatment of brain tumors, arteriovenous malformation, and functional conditions. However, radiation-induced therapeutic effect in viable cells in functional SRS is also suggested. Evaluation of the proposed modulatory effect of irradiation on neuronal activity without causing cellular death requires the knowledge of radiation dose tolerance at very small tissue volume. Therefore, we aimed to establish a porcine model to study the effects of ultra-high radiosurgical doses in small volumes of the brain. Five minipigs received focal stereotactic radiosurgery with single large doses of 40-100 Gy to 5-7.5 mm fields in the left primary motor cortex and the right subcortical white matter, and one animal remained as unirradiated control. The animals were followed-up with serial MRI, PET scans, and histology 6 months post-radiation. We observed a dose-dependent relation of the histological and MRI changes at 6 months post-radiation. The necrotic lesions were seen in the grey matter at 100 Gy and in white matter at 60 Gy. Furthermore, small volume radiosurgery at different dose levels induced vascular, as well as neuronal cell changes and glial cell remodeling.

Scheduled bright light for treatment of insomnia in older adults.

OBJECTIVES: To determine whether bright light can improve sleep in older individuals with insomnia. DESIGN: Single-blind, placebo-controlled, 12-week, parallel-group randomized design comparing four treatment groups representing a factorial combination of two lighting conditions and two times of light administration. SETTING: At-home light treatment; eight office therapy sessions. PARTICIPANTS: Thirty-six women and fifteen men (aged 63.6+/-7.1) meeting primary insomnia criteria recruited from the community. INTERVENTION: A 12-week program of sleep hygiene and exposure to bright ( approximately 4,000 lux) or dim light ( approximately 65 lux) scheduled daily in the morning or evening for 45 minutes. MEASUREMENTS: Within-group changes were observed for subjective (sleep logs, questionnaires) and objective (actigraphy, polysomnography) sleep measures after morning or evening bright light. RESULTS: Within-group changes for subjective sleep measures after morning or evening bright light were not significantly different from those observed after exposure to scheduled dim light. Objective sleep changes (actigraphy, polysomnography) after treatment were not significantly different between the bright and dim light groups. Scheduled light exposure was able to shift the circadian phase predictably but was unrelated to changes in objective or subjective sleep measures. A polymorphism in CLOCK predicted morningness but did not moderate the effects of light on sleep. The phase angle between the circadian system (melatonin midpoint) and sleep (darkness) predicted the magnitude of phase delays, but not phase advances, engendered by bright light. CONCLUSION: Except for one subjective measure, scheduled morning or evening bright light effects were not different from those of scheduled dim light. Thus, support was not found for bright light treatment of older individuals with primary insomnia.

Should one use medications in combination with cognitive training? If so, which ones?

In this article, we review current research regarding diagnosis of cognitive impairment in nondemented adults and discuss why medications and cognitive training together may be more beneficial than either alone. We also review potential cognitive enhancers and future research challenges. There are major reasons for such research: (a) Large numbers of older adults without dementia but with cognitive problems are not treatable with current cognitive training techniques; (b) some medications offer a rationale (i.e., cognitive enhancement) and some evidence that they might be a useful adjunct; and (c) there are unanswered questions about which population to target, which medications to use, how to administer them, and issues regarding tolerance and use of appropriate (active) placebo controls. As the number of cognitively impaired older adults grows, it is likely that there will be pressure to treat more broadly with both medications and cognitive training.

Strategies to reduce site differences in multisite studies: a case study of Alzheimer disease progression.

OBJECTIVES: The objectives of this study were to evaluate the magnitude and sources of site differences in a multisite study of rates of cognitive decline among patients with Alzheimer disease and to seek strategies to reduce the magnitude of site differences in this and future such studies. METHODS: A total of 3,280 participants from 15 different sites was analyzed. For each participant, the average rate of change in the Mini-Mental State Examination (MMSE) was calculated. Participants who declined at least three MMSE points per year were classified "rapid decliners." Site differences in sociodemographic distributions and the percentage of rapid decliners were examined, and a signal detection approach was used to identify the main correlates of rapid decline. RESULTS: The percentage of rapid decliners for the 15 sites initially varied from 8%-40%. Two of the correlates of rapid decline were largely the result of different sampling protocols, namely baseline MMSE and elapsed time between the first and last MMSE. By selecting only those participants at each site with a baseline MMSE between 15 and 23, and limiting the follow-up time to a period of 11-24 months, the authors created greater homogeneity in the protocols across sites and reduced site variability of rapid decliners from 27%-50%. CONCLUSION: Results of single-site studies are often nonreproducible, and multisite studies that follow different protocols and do not take site differences into account may be misleading. This study indicates the importance of site differences and how relatively simple efforts to impose common sampling, measurement, and design criteria can reduce, if not totally remove, site differences.

Factors in choosing atypical antipsychotics: toward understanding the bases of physicians' prescribing decisions.

OBJECTIVE: Off-label prescribing of medications, polypharmacy, and other questionable prescribing practices have led investigators to examine a large VA pharmacy database to determine if physician prescribing decisions appear reasonable. METHOD: The current study addresses the question of physician prescribing of atypical antipsychotics in 34,925 veterans with schizophrenia, using a series of signal detection analyses. RESULTS: These results suggest that only three factors (hospital size, age, and secondary diagnosis) allow classification of patients prescribed atypicals into three groups with frequencies of use of atypicals ranging from 43% to 79%, and that these results are consistent with reasonable clinical practice. CONCLUSIONS: Results of two-stage signal detection analyses are readily interpretable by clinicians and administrators who are faced with the task of evaluating how physicians prescribe medications in clinical practice. Physicians' decisions to prescribe atypical antipsychotics are based on both patient and fiscal considerations. This likely reflects a combination of clinical judgment and institutional guidelines.

Genome-wide mutagenesis of Zea mays L. using RescueMu transposons.

Derived from the maize Mu1 transposon, RescueMu provides strategies for maize gene discovery and mutant phenotypic analysis. 9.92 Mb of gene-enriched sequences next to RescueMu insertion sites were co-assembled with expressed sequence tags and analyzed. Multiple plasmid recoveries identified probable germinal insertions and screening of RescueMu plasmid libraries identified plants containing probable germinal insertions. Although frequently recovered parental insertions and insertion hotspots reduce the efficiency of gene discovery per plasmid, RescueMu targets a large variety of genes and produces knockout mutants.