Effect of vitamin E and memantine on functional decline in Alzheimer disease: the TEAM-AD VA cooperative randomized trial.

IMPORTANCE: Although vitamin E and memantine have been shown to have beneficial effects in moderately severe Alzheimer disease (AD), evidence is limited in mild to moderate AD. OBJECTIVE: To determine if vitamin E (alpha tocopherol), memantine, or both slow progression of mild to moderate AD in patients taking an acetylcholinesterase inhibitor. DESIGN, SETTING, AND PARTICIPANTS: Double-blind, placebo-controlled, parallel-group, randomized clinical trial involving 613 patients with mild to moderate AD initiated in August 2007 and concluded in September 2012 at 14 Veterans Affairs medical centers. INTERVENTIONS: Participants received either 2000 IU/d of alpha tocopherol (n = 152), 20 mg/d of memantine (n = 155), the combination (n = 154), or placebo (n = 152). MAIN OUTCOMES AND MEASURES: Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) Inventory score (range, 0-78). Secondary outcomes included cognitive, neuropsychiatric, functional, and caregiver measures. RESULTS: Data from 561 participants were analyzed (alpha tocopherol = 140, memantine = 142, combination = 139, placebo = 140), with 52 excluded because of a lack of any follow-up data. Over the mean (SD) follow-up of 2.27 (1.22) years, ADCS-ADL Inventory scores declined by 3.15 units (95% CI, 0.92 to 5.39; adjusted P = .03) less in the alpha tocopherol group compared with the placebo group. In the memantine group, these scores declined 1.98 units less (95% CI, -0.24 to 4.20; adjusted P = .40) than the placebo group's decline. This change in the alpha tocopherol group translates into a delay in clinical progression of 19% per year compared with placebo or a delay of approximately 6.2 months over the follow-up period. Caregiver time increased least in the alpha tocopherol group. All-cause mortality and safety analyses showed a difference only on the serious adverse event of "infections or infestations," with greater frequencies in the memantine (31 events in 23 participants) and combination groups (44 events in 31 participants) compared with placebo (13 events in 11 participants). CONCLUSIONS AND RELEVANCE: Among patients with mild to moderate AD, 2000 IU/d of alpha tocopherol compared with placebo resulted in slower functional decline. There were no significant differences in the groups receiving memantine alone or memantine plus alpha tocopherol. These findings suggest benefit of alpha tocopherol in mild to moderate AD by slowing functional decline and decreasing caregiver burden. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00235716.

Vitamin E and memantine in Alzheimer's disease: clinical trial methods and baseline data.

BACKGROUND: Alzheimer's disease (AD) has been associated with both oxidative stress and excessive glutamate activity. A clinical trial was designed to compare the effectiveness of (i) alpha-tocopherol, a vitamin E antioxidant; (ii) memantine (Namenda), an N-methyl-D-aspartate antagonist; (iii) their combination; and (iv) placebo in delaying clinical progression in AD. METHODS: The Veterans Affairs Cooperative Studies Program initiated a multicenter, randomized, double-blind, placebo-controlled trial in August 2007, with enrollment through March 2012 and follow-up continuing through September 2012. Participants with mild-to-moderate AD who were taking an acetylcholinesterase inhibitor were assigned randomly to 2000 IU/day of alpha-tocopherol, 20 mg/day memantine, 2000 IU/day alpha-tocopherol plus 20 mg/day memantine, or placebo. The primary outcome for the study is the Alzheimer's Disease Cooperative Study/Activities of Daily Living Inventory. Secondary outcome measures include the Mini-Mental State Examination; the Alzheimer's Disease Assessment Scale, cognitive portion; the Dependence Scale; the Neuropsychiatric Inventory; and the Caregiver Activity Survey. Patient follow-up ranged from 6 months to 4 years. RESULTS: A total of 613 participants were randomized. The majority of the patients were male (97%) and white (86%), with a mean age of 79 years. The mean Alzheimer's Disease Cooperative Study/Activities of Daily Living Inventory score at entry was 57 and the mean Mini-Mental State Examination score at entry was 21. CONCLUSION: This large multicenter trial will address the unanswered question of the long-term safety and effectiveness of alpha-tocopherol, memantine, and their combination in patients with mild-to-moderate AD taking an acetylcholinesterase inhibitor. The results are expected in early 2013.

Neurochemical and behavioral profiling of the selective GlyT1 inhibitors ALX5407 and LY2365109 indicate a preferential action in caudal vs. cortical brain areas.

Selective inhibitors of the glycine transporter 1 (GlyT1) have been implicated in central nervous system disorders related to hypoglutamatergic function such as schizophrenia. The selective GlyT1 inhibitors ALX5407 (NFPS) and LY2365109 {[2-(4-benzo[1,3]dioxol-5-yl-2-tert-butylphenoxy)ethyl]-methylamino}-acetic acid increased cerebrospinal fluid levels of glycine and potentiated NMDA-induced increases in dialysate levels of neurotransmitters in the prefrontal cortex (PFC) and the striatum. However, higher doses produced both stimulatory and inhibitory effects on motor performance and impaired respiration, suggesting significant involvement of cerebellar and brain stem areas. A dual probe microdialysis study showed that ALX5407 transiently elevated extracellular levels of glycine in the PFC with more sustained increases in the cerebellum. In support of these findings, immuno-staining with pan-GlyT1 and GlyT1a antibodies showed a higher abundance of immunoreactivity in the brain stem/cerebellum as compared to the frontal cortical/hippocampal brain areas in four different species studied, including the mouse, rat, monkey and human. In addition, the inhibitory effects of ALX5407 on cerebellar levels of cGMP in the mouse could be reversed by the glycine A receptor antagonist strychnine but not the glycine B receptor antagonist L-701324. We propose that the adverse events seen with higher doses of ALX5407 and LY2365109 are the result of high GlyT1 inhibitory activity in caudal areas of the brain with sustained elevations of extracellular glycine. High levels of glycine in these brain areas may result in activation of strychnine-sensitive glycine A receptors that are inhibitory on both motor activity and critical brain stem functions such as respiration.

Respiratory protection competencies for the occupational health nurse.

Approximately 5 million workers employed at 1.3 million work settings are required to wear some form of respiratory protection as part of their jobs. Occupational health nurses can protect the respiratory health of America's workforce. In 2012, the American Association of Occupational Health Nurses Grants Committee Working Group conducted a nationwide survey of occupational health nurses to assess their knowledge, comfort, skills, and abilities relative to respiratory protection. The Working Group used the survey findings as a foundation for the development of respiratory protection competencies for occupational health nurses and a guide for the development of educational modules.

Comparison of fentanyl and morphine in laser surgery for retinopathy of prematurity.

PURPOSE: To compare complication rates of the analgesics fentanyl and morphine in preterm infants undergoing laser therapy for retinopathy of prematurity (ROP). METHODS: In this observational study, the medical records of consecutive preterm neonates undergoing laser treatment of ROP from June 2007 through September 2010 were retrospectively reviewed. Because a fentanyl-based infusion protocol was initiated in November 2009, there was approximately the same number of treatment sessions with morphine and with fentanyl. In both groups, midazolam was used additionally on a case-by-case basis. Analgesia type, complications, and vital signs were documented at 5-minute intervals for all surgeries. The primary outcome was change in ventilation status. Secondary complications included change in temperature and incidence of apneic, bradycardic, and desaturation events. RESULTS: A total of 35 patients were included, with 17 in the morphine group (mean gestational age, 24.8 weeks; mean birth weight, 661 g) and 18 in the fentanyl group (mean gestational age, 24.4 weeks; mean birth weight, 681 g). Overall worsening of ventilation status was noted in 29% of patients in the morphine group and 6% of patients in the fentanyl group (P = 0.08; 95% confidence interval, -2% to 48%). Temperature instability (outside of 36.5° to 37.4°C range) was noted in 6% of patients in the morphine group and no patients in the fentanyl group. Apneic events were 3.2 times more common and bradycardic events 1.5 times more common in the morphine group. CONCLUSIONS: We found no difference in safety parameters for fentanyl infusion or morphine for analgesia in preterm infants undergoing ROP laser therapy in the neonatal intensive care unit setting. Although estimates of complication rates suggest that fentanyl may be safer, further study is needed to confirm this premise.

The relationship of external and internal sidewall dimensions in the adult Caucasian nose.

OBJECTIVES/HYPOTHESES: Nasal bone length is commonly referenced in the rhinoplasty literature. It has been suggested that short nasal bone length may predispose one to a greater risk of middle vault collapse after rhinoplasty. However, there are limited data available on what constitutes the normal dimensions of these pertinent structures of the nasal sidewall. In addition, no data exist on the gender and ethnic variability of such dimensions. This article reports on measurements of nasal bones and associated structures in adult Caucasian cadavers and their relationships to the nasal sidewall. Furthermore, this study assesses the validity of using surface measurements to approximate the true dimensions of the nasal sidewall structures. METHODS: Using 37 adult cadavers, stable, external, nasal landmarks were identified and measured to approximate the dimensions of the nasal bones and upper lateral cartilages. These clinically relevant surface landmarks were then evaluated relative to the direct measurements of dissected nasal bones and upper lateral cartilages in a subgroup of 14 cadavers. RESULTS: For the subgroup, the average length Ainternal (nasal bone) was 24.57 mm; the average measured length Binternal (upper lateral cartilage) was 12.43 mm. Measurements for the subgroup obtained via external landmarks were 20.21 mm (Aexternal) and 15.67 mm (Bexternal), respectively. The relationship of the nasal bone internal length to the external measurement (A) was a ratio of 1.22:1, whereas the internal length of the upper lateral cartilage to the corresponding external measurement (B) was 0.79:1. Average external measurements for the total group were 20.43 mm for the nasal bone and 14.30 mm for the upper lateral cartilage. CONCLUSIONS: These data provide useful information to guide the surgeon in avoiding middle vault collapse postoperatively and when evaluating those patients with presurgical middle vault concerns. With less ability to support the upper lateral cartilages, short nasal bones can predispose an individual to middle vault collapse postoperatively.

Persistent Psychosis and Medical Complications After a Single Ingestion of MDMA "Ecstasy": A Case Report and Review of the Literature.

We describe a case report of persistent psychosis and severe medical complications in a previously healthy, 19-year-old African-American man after a single ingestion of what was purported to be "Ecstasy." We detail the psychiatric symptoms and medical complications that resulted in several weeks of hospitalization in both medical intensive care and psychiatric units. Furthermore, we describe changes in the demographics of the use of Ecstasy and present the current understanding of the cause of neurotoxicity after Ecstasy use when it occurs. We conclude by suggesting actions clinicians can take to ameliorate the negative consequences of Ecstasy use.

Discovery and SAR studies of novel GlyT1 inhibitors.

Inhibition of the glycine transporter GlyT1 is a potential strategy for the treatment of schizophrenia. A novel series of GlyT1 inhibitors and their structure-activity relationships (SAR) are described. Members of this series are highly potent and selective transport inhibitors which are shown to elevate glycine levels in cerebrospinal fluid.