Synergistic effects of long-term antioxidant diet and behavioral enrichment on beta-amyloid load and non-amyloidogenic processing in aged canines.

A long-term intervention (2.69 years) with an antioxidant diet, behavioral enrichment, or the combined treatment preserved and improved cognitive function in aged canines. Although each intervention alone provided cognitive benefits, the combination treatment was additive. We evaluate the hypothesis that antioxidants, enrichment, or the combination intervention reduces age-related beta-amyloid (Abeta) neuropathology, as one mechanism mediating observed functional improvements. Measures assessed were Abeta neuropathology in plaques, biochemically extractable Abeta(40) and Abeta(42) species, soluble oligomeric forms of Abeta, and various proteins in the beta-amyloid precursor protein (APP) processing pathway. The strongest and most consistent effects on Abeta pathology were observed in animals receiving the combined antioxidant and enrichment treatment. Specifically, Abeta plaque load was significantly decreased in several brain regions, soluble Abeta(42) was decreased selectively in the frontal cortex, and a trend for lower Abeta oligomer levels was found in the parietal cortex. Reductions in Abeta may be related to shifted APP processing toward the non-amyloidogenic pathway, because alpha-secretase enzymatic activity was increased in the absence of changes in beta-secretase activity. Although enrichment alone had no significant effects on Abeta, reduced Abeta load and plaque maturation occurred in animals receiving antioxidants as a component of treatment. Abeta measures did not correlate with cognitive performance on any of the six tasks assessed, suggesting that modulation of Abeta alone may be a relatively minor mechanism mediating cognitive benefits of the interventions. Overall, the data indicate that multidomain treatments may be a valuable intervention strategy to reduce neuropathology and improve cognitive function in humans.

A two-year study with fibrillar beta-amyloid (Abeta) immunization in aged canines: effects on cognitive function and brain Abeta.

Aged canines (dogs) accumulate human-type beta-amyloid (Abeta) in diffuse plaques in the brain with parallel declines in cognitive function. We hypothesized that reducing Abeta in a therapeutic treatment study of aged dogs with preexisting Abeta pathology and cognitive deficits would lead to cognitive improvements. To test this hypothesis, we immunized aged beagles (8.4-12.4 years) with fibrillar Abeta(1-42) formulated with aluminum salt (Alum) for 2.4 years (25 vaccinations). Cognitive testing during this time revealed no improvement in measures of learning, spatial attention, or spatial memory. After extended treatment (22 vaccinations), we observed maintenance of prefrontal-dependent reversal learning ability. In the brain, levels of soluble and insoluble Abeta(1-40) and Abeta(1-42) and the extent of diffuse plaque accumulation was significantly decreased in several cortical regions, with preferential reductions in the prefrontal cortex, which is associated with a maintenance of cognition. However, the amount of soluble oligomers remained unchanged. The extent of prefrontal Abeta was correlated with frontal function and serum anti-Abeta antibody titers. Thus, reducing total Abeta may be of limited therapeutic benefit to recovery of cognitive decline in a higher mammalian model of human brain aging and disease. Immunizing animals before extensive Abeta deposition and cognitive decline to prevent oligomeric or fibrillar Abeta formation may have a greater impact on cognition and also more directly evaluate the role of Abeta on cognition in canines. Alternatively, clearing preexisting Abeta from the brain in a treatment study may be more efficacious for cognition if combined with a second intervention that restores neuron health.

Aseptic meningitis in infants younger than six months of age hospitalized with urinary tract infections.

BACKGROUND: Aseptic meningitis associated with urinary tract infection (UTI) in young infants has not been described in detail in the literature. We performed a retrospective study to determine the incidence and clinical features of aseptic meningitis accompanying UTI. METHODS: We retrospectively reviewed the medical records of all infants younger than 6 months of age hospitalized with a UTI at Miller Children's Hospital from March 1995 through March 2000. UTI was defined as a urine culture growing > or =10,000 colony-forming units/ml of a single organism from a catheterized specimen or > or =100,000 colony-forming units/ml of a single organism from a bagged urine specimen. Meningitis was defined as a positive cerebrospinal fluid culture or cerebrospinal fluid with >35 white blood cells/mm3 in infants < or =30 days of age or with >10 white blood cells/mm3 in infants >30 days of age. RESULTS: Of 386 infants with UTI, a lumbar puncture was performed in 260, and 31 (11.9%) had aseptic meningitis. One infant had bacterial meningitis. None of the 26 infants with UTI and bacteremia had aseptic meningitis. Two infants with meningitis had confirmed enteroviral infections, but aseptic meningitis did not occur more frequently in any particular month or during times of peak enteroviral activity. CONCLUSIONS: A cerebrospinal fluid pleocytosis is relatively common in hospitalized infants <6 months of age who have a UTI and usually does not reflect bacterial meningitis. Knowledge of this may prevent unnecessary courses of antibiotics for presumed bacterial meningitis and lead to evaluation for other possible causes of aseptic meningitis including viral or congenital infections.

Systemic vs. local cytokine and leukocyte responses to unilateral wrist flexion exercise.

We hypothesized that brief exercise of a small muscle group would lead to local rather than systemic alterations in cytokines, peripheral blood mononuclear cells, and mediators of angiogenesis. Fifteen men and eight women (age range 22-36 yr old) performed 10 min of unilateral wrist flexion exercise. Blood was sampled from venous catheters in the resting and exercising arm at baseline, at the end of exercise, and at 10, 30, 60, and 120 min after exercise. Lactate was significantly elevated in the exercising arm (+276 +/- 35%; P < 0.0005) with no change in the resting arm. In contrast, increases in both arms were observed for interleukin-6 (+139 +/- 51%; P < 0.0005), growth hormone (+1,104 +/- 284%; P < 0.003), natural killer cells (+81 +/- 9%; P < 0.0005), and lymphocytes expressing CD62L, CD11a, and CD54. There were no significant differences in these increases between the resting and exercising arm. Catecholamines increased in both arms [epinephrine peak increase, +226 +/- 36% (P < 0.001); norepinephrine peak increase, +90 +/- 15% (P < 0.01)]. Fibroblast growth factor-2 initially decreased with exercise in both arms, and this was followed by a rebound increase. Vascular endothelial growth factor demonstrated a small but significant increase in both arms (+124 +/- 31%; P < 0.05). Brief, low-intensity exercise leads to a systemic rather than local response of mediators that could be involved in inflammation, repair, or angiogenic adaptation to physical activity.

Refractive change in response to acute hyperbaric stress in refractive surgery patients.

PURPOSE: To determine whether acute hyperbaric stress affects visual acuity or refractive power after keratorefractive surgery. SETTING: Clinical multiplace hyperbaric chamber and ophthalmology clinic, University of California, San Diego, California, USA. METHODS: This prospective convenience sample study included 3 groups: 3 patients who had had bilateral myopic radial keratotomy (RK); 2 who had had bilateral myopic laser in situ keratomileusis (LASIK); and 4 control subjects who had no previous corneal refractive surgery or ocular pathology but had a myopic refractive error (-1.25 to -8.38 diopters [D]) similar to that in the treated patients before refractive surgery. One additional patient had had unilateral LASIK only and was included in the LASIK and control groups. Best spectacle-corrected visual acuity (BSCVA), manifest spherocylindrical refractive error, and intraocular pressure were measured at baseline, at 4 atmospheres absolute (atm abs), and on return to ambient pressure. Corneal pachymetry and keratometry were measured at baseline and on return to ambient pressure. RESULTS: The mean BSCVA changed from 0.06 logMAR (20/25 Snellen equivalent) at baseline to 0.10 logMAR (20/25) at 4 atm abs in the RK group and from 0.00 logMAR (20/20) to -0.06 logMAR (20/15) in the LASIK group; it did not change in the control group. The mean refractive error changed from 0.25 D at baseline to 0.50 D at 4 atm abs in the RK group, from -0.90 to -1.02 D in the LASIK group, and from -4.58 to -4.53 D in the control group. CONCLUSIONS: Acute hyperbaric stress did not appear to alter refractive power after corneal surgery.

Impact of high-intensity exercise on nitric oxide exchange in healthy adults.

PURPOSE: After exercise, exhaled NO concentration has been reported to decrease, remain unchanged, or increase. A more mechanistic understanding of NO exchange dynamics after exercise is needed to understand the relationship between exercise and NO exchange. METHODS: We measured several flow-independent NO exchange parameters characteristic of airway and alveolar regions using a single breath maneuver and a two-compartment model (maximum flux of NO from the airways, J'(awNO), pL x s-1; diffusing capacity of NO in the airways, D(awNO), pL x s-1 x ppb-1; steady state alveolar concentration, C(alv,ss), ppb; mean airway tissue NO concentration, C(awNO), ppb), as well as serum IL-6 at baseline, 3, 30, and 120 min after a high-intensity exercise challenge in 10 healthy adults (21-37 yr old). RESULTS: D(awNO) (mean +/- SD) increased (37.1 +/- 44.4%), whereas J'(awNO) and C(awNO) decreased (-7.27 +/- 11.1%, -26.1 +/- 24.6%, respectively) 3 min postexercise. IL-6 increased steadily after exercise to 481% +/- 562% above baseline 120 min postexercise. CONCLUSION: High-intensity exercise acutely enhances the ability of NO to diffuse between the airway tissue and the gas phase, and exhaled NO might be used to probe both the metabolic and physical properties of the airways.

A randomized clinical trial to assess the efficacy of the Epley maneuver in the treatment of acute benign positional vertigo.

OBJECTIVES: To compare the efficacy of the Epley maneuver with that of a placebo maneuver in patients presenting to the emergency department (ED) with benign positional vertigo (BPV). METHODS: This was a prospective, randomized, single-blind placebo-controlled trial. Consecutive adult ED patients presenting to a university teaching hospital with BPV were randomized to treatment with either the Epley or placebo maneuver. The severity of vertigo was evaluated on a 0 to 10-point scale before and after the maneuvers. RESULTS: Eleven patients were randomized to the Epley group and 11 to the placebo group before the trial was terminated, based on a planned interim analysis. The median decreases in vertigo severity were 6 (95% confidence interval [95% CI] = 4 to 9) for the Epley group and 1 (95% CI = 0 to 3) for the placebo group (p = 0.001). CONCLUSIONS: The Epley maneuver is a simple bedside maneuver that appears to be more efficacious than a placebo maneuver in the treatment of acute BPV among ED patients.

Plasma amyloid-ß as a function of age, level of intellectual disability, and presence of dementia in Down syndrome.

Adults with Down syndrome (DS) are at risk for developing Alzheimer's disease (AD). While plasma amyloid-ß (Aß) is known to be elevated in DS, its relationship to cognitive functioning is unknown. To assess this relationship, samples from two groups of subjects were used. In the first group, nondemented adults with DS were compared to: 1) a group of young and old individuals without DS and 2) to a group of patients with AD. Compared to these controls, there were significantly higher levels of plasma Aß in nondemented adults with DS while AD patients showed lower levels of plasma Aß. A larger second group included demented and nondemented adults with DS, in order to test the hypothesis that plasma Aß may vary as a function of dementia and Apolipoprotein E (ApoE) genotype. Plasma Aß levels alone did not dissociate DS adults with and without dementia. However, in demented adults with DS, ApoE4 was associated with higher Aß40 but not Aß42. After controlling for level of intellectual disability (mild, moderate, severe) and the presence or absence of dementia, there was an improved prediction of neuropsychological scores by plasma Aß. In summary, plasma Aß can help predict cognitive function in adults with DS independently of the presence or absence of dementia.

A survey of voiding dysfunction in children with attention deficit-hyperactivity disorder.

PURPOSE: Physicians treating attention deficit-hyperactivity disorder (ADHD) have long had the clinical impression that these children suffer disproportionately from voiding dysfunction and incontinence. However, no data exist to confirm this suspicion. In an attempt to investigate this clinical finding, we administered a survey asking about any functional bladder symptoms to a group of children with ADHD and a control group without ADHD. MATERIALS AND METHODS: The Dysfunctional Voiding Symptom Survey (DVSS) was administered to a group of children being treated for rigorously diagnosed ADHD and a control group without ADHD. The DVSS consists of 10 questions that assess daytime incontinence, nocturnal enuresis, constipation, urgency, voiding frequency and dysuria, each scored from 0 to 4 (0-never, 1-almost never, 2-less than half the time, 3-about half the time, 4-almost every time) for a maximum total score of 40 (severest symptoms). Scores for patients and controls were compared for each question and in aggregate. Boys and girls underwent separate statistical analysis. An additional eleventh question assesses recent stressful events within the family. RESULTS: The patient group included 23 boys and 5 girls, and the control group 10 boys and 12 girls. Children with ADHD of both sexes had statistically significant higher overall DVSS scores. Boys had significant differences on several questions. Due to the small number of girls, there were no statistically significant differences on individual questions. CONCLUSIONS: Children with ADHD have significantly higher rates of incontinence, constipation, urgency, infrequent voiding, nocturnal enuresis and dysuria than those without ADHD. Further study is needed to discern the cause of this difference and develop appropriate treatment strategies.

Effect of intense exercise on inflammatory cytokines and growth mediators in adolescent boys.

OBJECTIVE: Exercise can enhance growth and development in children, but recent investigations have revealed an intriguing paradox. Namely, the early (4-5 weeks) response to training programs in children lead to a catabolic, growth hormone (GH)-resistant state rather than the expected anabolic activation of the GH-->insulin-like growth factor-I (IGF-I) axis. This paradox led us to hypothesize that single bouts of exercise in children could stimulate proinflammatory cytokines known to inhibit directly anabolic activity of the GH-->IGF-1 axis (interleukin [IL]-6, IL-1beta, and tumor necrosis factor-alpha [TNF-alpha]). METHODS: Eleven healthy high school-age boys, age 14 to 18.5 years, performed a single, typical, 1.5-hour wrestling practice session. Blood was sampled before and after the session. RESULTS: We found significant decreases in anabolic mediators: total IGF-I (-11.2 +/- 2.3%), bound IGF-I (-11.2 +/- 2.4%), and insulin (-42 +/- 10%. However, there was no change in unbound IGF-I. Remarkable increases were found in proinflammatory cytokines IL-6 (795 +/- 156%), TNF-alpha (30 +/- 12%), and IL-1beta (286 +/- 129%) and in IGF-binding protein-1 (835 +/- 234%), which itself is stimulated by inflammatory cytokines and is known to inhibit IGF-I. Evidence for compensatory mechanisms to counter the antianabolic inflammatory response to acute exercise were also noted: IL-1ra increased (80 +/- 20%) and IGF-binding protein-3 proteolysis (which can maintain unbound, biologically active IGF-I despite losses in total IGF-I) increased significantly (101 +/- 39%) as well. CONCLUSIONS: These data demonstrate that an intense exercise bout in male adolescents leads to reductions in anabolic mediators and profound increases in inflammatory cytokines. This might explain the development of what seems to be a paradoxical catabolic state in the initial phases of exercise training programs.

The state of ED on-call coverage in California.

The ED provides initial treatment, but failure of specialists to respond unravels the safety net. To assess the scope of problems with on-call physicians in California. A mailed anonymous survey to all CAL/ACEP physician members (1876) asking patient, physician and ED demographics, specialist availability for consultation, insurance profile, and availability of follow-up care. 608/1876 physicians responded (32.4%), representing 320/353 California EDs (90.6%). The seven specialties in which the greatest proportion of EDs reported trouble with specialty response were: plastic surgery (37.5%), ENT (35.9%), dentistry (34.9%), psychiatry (26.0%), neurosurgery (22.9%), ophthalmology (18.4%) and orthopedics (18.0%). 71.6% of responder EDs reported that their medical staff rules required ED on-call coverage. However, the percentage of responders who stated that hospitals paid each specialty for call was low: neurosurgery (37.3%), orthopedics (34.4%), ENT (17.9%), plastic surgery (15.1%) and ophthalmology (13.1%). On-call problems were more acute at night (77.2%) or on weekends (72.4%). Patient insurance negatively affected (69.9%) willingness of on-call physicians to consult for at least a quarter of patients. Regarding follow-up, 91% reported some trouble, whereas 64% reported a problem at least half the time. Surgical sub-specialists are the most problematic on-call physicians. Insurance status has a major negative effect on ED and follow-up care. The on-call situation in California has reached crisis proportions.