Traumatic brain injury exacerbates neurodegenerative pathology: improvement with an apolipoprotein E-based therapeutic.

Cognitive impairment is common following traumatic brain injury (TBI), and neuroinflammatory mechanisms may predispose to the development of neurodegenerative disease. Apolipoprotein E (apoE) polymorphisms modify neuroinflammatory responses, and influence both outcome from acute brain injury and the risk of developing neurodegenerative disease. We demonstrate that TBI accelerates neurodegenerative pathology in double-transgenic animals expressing the common human apoE alleles and mutated amyloid precursor protein, and that pathology is exacerbated in the presence of the apoE4 allele. The administration of an apoE-mimetic peptide markedly reduced the development of neurodegenerative pathology in mice homozygous for apoE3 as well as apoE3/E4 heterozygotes. These results demonstrate that TBI accelerates the cardinal neuropathological features of neurodegenerative disease, and establishes the potential for apoE mimetic therapies in reducing pathology associated with neurodegeneration.

Spatial vision in the purple sea urchin Strongylocentrotus purpuratus (Echinoidea).

Recent evidence that echinoids of the genus Echinometra have moderate visual acuity that appears to be mediated by their spines screening off-axis light suggests that the urchin Strongylocentrotus purpuratus, with its higher spine density, may have even more acute spatial vision. We analyzed the movements of 39 specimens of S. purpuratus after they were placed in the center of a featureless tank containing a round, black target that had an angular diameter of 6.5 deg. or 10 deg. (solid angles of 0.01 sr and 0.024 sr, respectively). An average orientation vector for each urchin was determined by testing the animal four times, with the target placed successively at bearings of 0 deg., 90 deg., 180 deg. and 270 deg. (relative to magnetic east). The urchins showed no significant unimodal or axial orientation relative to any non-target feature of the environment or relative to the changing position of the 6.5 deg. target. However, the urchins were strongly axially oriented relative to the changing position of the 10 deg. target (mean axis from -1 to 179 deg.; 95% confidence interval +/- 12 deg.; P<0.001, Moore's non-parametric Hotelling's test), with 10 of the 20 urchins tested against that target choosing an average bearing within 10 deg. of either the target center or its opposite direction (two would be expected by chance). In addition, the average length of the 20 target-normalized bearings for the 10 deg. target (each the vector sum of the bearings for the four trials) were far higher than would be expected by chance (P<10(-10); Monte Carlo simulation), showing that each urchin, whether it moved towards or away from the target, did so with high consistency. These results strongly suggest that S. purpuratus detected the 10 deg. target, responding either by approaching it or fleeing it. Given that the urchins did not appear to respond to the 6.5 deg. target, it is likely that the 10 deg. target was close to the minimum detectable size for this species. Interestingly, measurements of the spine density of the regions of the test that faced horizontally predicted a similar visual resolution (8.3+/-0.5 deg. for the interambulacrum and 11+/-0.54 deg. for the ambulacrum). The function of this relatively low, but functional, acuity - on par with that of the chambered Nautilus and the horseshoe crab - is unclear but, given the bimodal response, is likely to be related to both shelter seeking and predator avoidance.

Altered ultrasonic vocalization and impaired learning and memory in Angelman syndrome mouse model with a large maternal deletion from Ube3a to Gabrb3.

Angelman syndrome (AS) is a neurobehavioral disorder associated with mental retardation, absence of language development, characteristic electroencephalography (EEG) abnormalities and epilepsy, happy disposition, movement or balance disorders, and autistic behaviors. The molecular defects underlying AS are heterogeneous, including large maternal deletions of chromosome 15q11-q13 (70%), paternal uniparental disomy (UPD) of chromosome 15 (5%), imprinting mutations (rare), and mutations in the E6-AP ubiquitin ligase gene UBE3A (15%). Although patients with UBE3A mutations have a wide spectrum of neurological phenotypes, their features are usually milder than AS patients with deletions of 15q11-q13. Using a chromosomal engineering strategy, we generated mutant mice with a 1.6-Mb chromosomal deletion from Ube3a to Gabrb3, which inactivated the Ube3a and Gabrb3 genes and deleted the Atp10a gene. Homozygous deletion mutant mice died in the perinatal period due to a cleft palate resulting from the null mutation in Gabrb3 gene. Mice with a maternal deletion (m-/p+) were viable and did not have any obvious developmental defects. Expression analysis of the maternal and paternal deletion mice confirmed that the Ube3a gene is maternally expressed in brain, and showed that the Atp10a and Gabrb3 genes are biallelically expressed in all brain sub-regions studied. Maternal (m-/p+), but not paternal (m+/p-), deletion mice had increased spontaneous seizure activity and abnormal EEG. Extensive behavioral analyses revealed significant impairment in motor function, learning and memory tasks, and anxiety-related measures assayed in the light-dark box in maternal deletion but not paternal deletion mice. Ultrasonic vocalization (USV) recording in newborns revealed that maternal deletion pups emitted significantly more USVs than wild-type littermates. The increased USV in maternal deletion mice suggests abnormal signaling behavior between mothers and pups that may reflect abnormal communication behaviors in human AS patients. Thus, mutant mice with a maternal deletion from Ube3a to Gabrb3 provide an AS mouse model that is molecularly more similar to the contiguous gene deletion form of AS in humans than mice with Ube3a mutation alone. These mice will be valuable for future comparative studies to mice with maternal deficiency of Ube3a alone.

Alterations in cardiac adrenergic signaling and calcium cycling differentially affect the progression of cardiomyopathy.

The medical treatment of chronic heart failure has undergone a dramatic transition in the past decade. Short-term approaches for altering hemodynamics have given way to long-term, reparative strategies, including beta-adrenergic receptor (betaAR) blockade. This was once viewed as counterintuitive, because acute administration causes myocardial depression. Cardiac myocytes from failing hearts show changes in betaAR signaling and excitation-contraction coupling that can impair cardiac contractility, but the role of these abnormalities in the progression of heart failure is controversial. We therefore tested the impact of different manipulations that increase contractility on the progression of cardiac dysfunction in a mouse model of hypertrophic cardiomyopathy. High-level overexpression of the beta(2)AR caused rapidly progressive cardiac failure in this model. In contrast, phospholamban ablation prevented systolic dysfunction and exercise intolerance, but not hypertrophy, in hypertrophic cardiomyopathy mice. Cardiac expression of a peptide inhibitor of the betaAR kinase 1 not only prevented systolic dysfunction and exercise intolerance but also decreased cardiac remodeling and hypertrophic gene expression. These three manipulations of cardiac contractility had distinct effects on disease progression, suggesting that selective modulation of particular aspects of betaAR signaling or excitation-contraction coupling can provide therapeutic benefit.

Enhanced rewarding properties of morphine, but not cocaine, in beta(arrestin)-2 knock-out mice.

The reinforcing and psychomotor effects of morphine involve opiate stimulation of the dopaminergic system via activation of mu-opioid receptors (muOR). Both mu-opioid and dopamine receptors are members of the G-protein-coupled receptor (GPCR) family of proteins. GPCRs are known to undergo desensitization involving phosphorylation of the receptor and the subsequent binding of beta(arrestins), which prevents further receptor-G-protein coupling. Mice lacking beta(arrestin)-2 (beta(arr2)) display enhanced sensitivity to morphine in tests of pain perception attributable to impaired desensitization of muOR. However, whether abrogating muOR desensitization affects the reinforcing and psychomotor properties of morphine has remained unexplored. In the present study, we examined this question by assessing the effects of morphine and cocaine on locomotor activity, behavioral sensitization, conditioned place preference, and striatal dopamine release in beta(arr2) knock-out (beta(arr2)-KO) mice and their wild-type (WT) controls. Cocaine treatment resulted in very similar neurochemical and behavioral responses between the genotypes. However, in the beta(arr2)-KO mice, morphine induced more pronounced increases in striatal extracellular dopamine than in WT mice. Moreover, the rewarding properties of morphine in the conditioned place preference test were greater in the beta(arr2)-KO mice when compared with the WT mice. Thus, beta(arr2) appears to play a more important role in the dopaminergic effects mediated by morphine than those induced by cocaine.

Associations between BMI and home, school and route environmental exposures estimated using GPS and GIS: do we see evidence of selective daily mobility bias in children?

BACKGROUND: This study examined whether objective measures of food, physical activity and built environment exposures, in home and non-home settings, contribute to children's body weight. Further, comparing GPS and GIS measures of environmental exposures along routes to and from school, we tested for evidence of selective daily mobility bias when using GPS data. METHODS: This study is a cross-sectional analysis, using objective assessments of body weight in relation to multiple environmental exposures. Data presented are from a sample of 94 school-aged children, aged 5-11 years. Children's heights and weights were measured by trained researchers, and used to calculate BMI z-scores. Participants wore a GPS device for one full week. Environmental exposures were estimated within home and school neighbourhoods, and along GIS (modelled) and GPS (actual) routes from home to school. We directly compared associations between BMI and GIS-modelled versus GPS-derived environmental exposures. The study was conducted in Mebane and Mount Airy, North Carolina, USA, in 2011. RESULTS: In adjusted regression models, greater school walkability was associated with significantly lower mean BMI. Greater home walkability was associated with increased BMI, as was greater school access to green space. Adjusted associations between BMI and route exposure characteristics were null. The use of GPS-actual route exposures did not appear to confound associations between environmental exposures and BMI in this sample. CONCLUSIONS: This study found few associations between environmental exposures in home, school and commuting domains and body weight in children. However, walkability of the school neighbourhood may be important. Of the other significant associations observed, some were in unexpected directions. Importantly, we found no evidence of selective daily mobility bias in this sample, although our study design is in need of replication in a free-living adult sample.

Effect of chronic angiotensin converting enzyme inhibition on spatial memory and anxiety-like behavours in rats

Angiotensin converting enzyme inhibitors (ACEis) are widely used anti-hypertensive agents that are also reported to have positive effects on mood and cognition. The present study examined the influence of the ACEi, perindopril, on cognitive performance and anxiety measures in rats. Two groups of rats were treated orally for one week with the ACEi, perindopril, at doses of 0.1 and 1.0mg/kg/day. Learning was assessed by the reference memory task in the water maze, comparing treated to control rats. Over five training days both perindopril-treated groups learnt the location of the submerged platform in the water maze task significantly faster than control rats. A 60s probe trial on day 6 showed that the 1.0mg/kg/day group spent significantly longer time in the training quadrant than control rats. This improved performance in the swim maze task was not due to the effect of perindopril on motor activity or the anxiety levels of the rats as perindopril-treated and control animals behaved similarly in activity boxes and on the elevated+maze. These results confirm the anecdotal human studies that ACEis have a positive influence on cognition and provide possibilities for ACEis to be developed into therapies for memory loss.

Physiological effects of platyhelminth FMRFamide-related peptides (FaRPs) on the motility of the monogenean Diclidophora merlangi

The actions of known platyhelminth FaRPs on the contractility of whole-worm preparations of the monogenean, Diclidophora merlangi have been examined in vitro for the first time. All of the peptides tested had excitatory effects on the motor activity of the worm. The order of potency for the peptides tested was: YIRFamide > GYIRFamide = RYIRFamide > GNFFRFamide = FLRFamide. However, although YIRFamide was more potent than GYIRFamide, the latter was the most efficacious on each of the motility parameters (tension, contraction amplitude and contraction frequency) examined at concentrations greater than or equal to 0.1 mu M. Serotonin, which stimulates contractility in the worm was used as a positive control. The excitatory activity of turbellarian and cestode neuropeptides on a monogenean indicates at least some structural similarities in the neuropeptide receptors of these classes of flatworm.

Encouraging lifestyle behaviour change in mild cognitive impairment patients:development of appropriate educational material

Objectives: A healthy lifestyle may help maintain cognitive function and reduce the risk of developing dementia. This study employed a focus group approach in order to gain insight into opinions of mild cognitive impairment (MCI) patients, caregivers (CG) and health professionals (HP) regarding lifestyle and its relationship with cognition. The qualitative data were used to design, develop and pilot test educational material (EM) to help encourage lifestyle behaviour change. Method: Data gathering phase: structured interviews were conducted with HP (n = 10), and focus groups with MCI patients (n = 24) and CG (n = 12). EM was developed and pilot tested with a new group of MCI patients (n = 21) and CG (n = 6). Results: HP alluded to the lack of clinical trial evidence for a lifestyle and MCI risk link. Although they felt that lifestyle modifications should be recommended to MCI patients, they appeared hesitant in communicating this information and discussions were often patient-driven. MCI patients lacked awareness of the lifestyle cognition link. Participants preferred EM to be concise, eye-catching and in written format, with personal delivery of information favoured. Most pilot testers approved of the EM but were heterogeneous in terms of lifestyle, willingness to change and support needed to change. Conclusion: MCI patients need to be made more aware of the importance of lifestyle for cognition. EM such as those developed here, which are specifically tailored for this population would be valuable for HP who, currently, appear reticent in initiating lifestyle-related discussions. Following further evaluation, the EM could be used in health promotion activities targeting MCI patients.

Spatiotemporal mechanisms for actomyosin ring assembly and contraction in budding yeast cell division

Dissertation presented to obtain the Ph.D degree in Molecular Medicine

Daily physical activities and sports in adult survivors of childhood cancer and healthy controls: a population-based questionnaire survey.

BACKGROUND: Healthy lifestyle including sufficient physical activity may mitigate or prevent adverse long-term effects of childhood cancer. We described daily physical activities and sports in childhood cancer survivors and controls, and assessed determinants of both activity patterns. METHODOLOGY/PRINCIPAL FINDINGS: The Swiss Childhood Cancer Survivor Study is a questionnaire survey including all children diagnosed with cancer 1976-2003 at age 0-15 years, registered in the Swiss Childhood Cancer Registry, who survived ≥5 years and reached adulthood (≥20 years). Controls came from the population-based Swiss Health Survey. We compared the two populations and determined risk factors for both outcomes in separate multivariable logistic regression models. The sample included 1058 survivors and 5593 controls (response rates 78% and 66%). Sufficient daily physical activities were reported by 52% (n = 521) of survivors and 37% (n = 2069) of controls (p<0.001). In contrast, 62% (n = 640) of survivors and 65% (n = 3635) of controls reported engaging in sports (p = 0.067). Risk factors for insufficient daily activities in both populations were: older age (OR for ≥35 years: 1.5, 95CI 1.2-2.0), female gender (OR 1.6, 95CI 1.3-1.9), French/Italian Speaking (OR 1.4, 95CI 1.1-1.7), and higher education (OR for university education: 2.0, 95CI 1.5-2.6). Risk factors for no sports were: being a survivor (OR 1.3, 95CI 1.1-1.6), older age (OR for ≥35 years: 1.4, 95CI 1.1-1.8), migration background (OR 1.5, 95CI 1.3-1.8), French/Italian speaking (OR 1.4, 95CI 1.2-1.7), lower education (OR for compulsory schooling only: 1.6, 95CI 1.2-2.2), being married (OR 1.7, 95CI 1.5-2.0), having children (OR 1.3, 95CI 1.4-1.9), obesity (OR 2.4, 95CI 1.7-3.3), and smoking (OR 1.7, 95CI 1.5-2.1). Type of diagnosis was only associated with sports. CONCLUSIONS/SIGNIFICANCE: Physical activity levels in survivors were lower than recommended, but comparable to controls and mainly determined by socio-demographic and cultural factors. Strategies to improve physical activity levels could be similar as for the general population.

D-amphetamine fails to increase extracellular dopamine levels in mice lacking alpha 1b-adrenergic receptors: relationship between functional and nonfunctional dopamine release.

It was found recently that locomotor and rewarding effects of psychostimulants and opiates were dramatically decreased or suppressed in mice lacking alpha1b-adrenergic receptors [alpha1b-adrenergic receptor knock-outs (alpha1bAR-KOs)] (Drouin et al., 2002). Here we show that blunted locomotor responses induced by 3 and 6 mg/kg d-amphetamine in alpha1bAR-KO mice [-84 and -74%, respectively, when compared with wild-type (WT) mice] are correlated with an absence of d-amphetamine-induced increase in extracellular dopamine (DA) levels in the nucleus accumbens of alpha1bAR-KO mice. Moreover, basal extracellular DA levels in the nucleus accumbens are lower in alpha1bAR-KO than in WT littermates (-28%; p < 0.001). In rats however, prazosin, an alpha1-adrenergic antagonist, decreases d-amphetamine-induced locomotor hyperactivity without affecting extracellular DA levels in the nucleus accumbens, a finding related to the presence of an important nonfunctional release of DA (Darracq et al., 1998). We show here that local d-amphetamine releases nonfunctional DA with the same affinity but a more than threefold lower amplitude in C57BL6/J mice than in Sprague Dawley rats. Altogether, this suggests that a trans-synaptic mechanism amplifies functional DA into nonfunctional DA release. Our data confirm the presence of a powerful coupling between noradrenergic and dopaminergic neurons through the stimulation of alpha1b-adrenergic receptors and indicate that nonfunctional DA release is critical in the interpretation of changes in extracellular DA levels. These results suggest that alpha1b-adrenergic receptors may be important therapeutic pharmacological targets not only in addiction but also in psychosis because most neuroleptics possess anti-alpha1-adrenergic properties.

Lésions de surcharge chez l'enfant [Overuse injuries in children].

The physical-activity and sporting at the child and the teenager is probably, in these years 2000, in full change. In a paradoxical way, extremely sporting children or teenagers are living beside extremely sedentary school-boys, neglecting the majority of the physical-activities and preferring a home-lifestyle. In the evaluation of overload sporting lesion of at teenager, it is thus imperative to take into account not only the individual characteristics of the child: its sex, its age, its stage of growth, its psychology, the presence or not of preexistent pathologies or anatomical disorders. It is naturally necessary to wonder about the training methods of the activity, but it appears fundamental to me to evaluate the child from a sensitivo-motor point of view and this can be carried out by assessments physio-therapeutic or aptitude tests carried out by doctors of the sport.

Metabolically healthy obesity: different prevalences using different criteria.

To estimate the prevalence of metabolically healthy obesity (MHO) according to different definitions. Population-based sample of 2803 women and 2557 men participated in the study. Metabolic abnormalities were defined using six sets of criteria, which included different combinations of the following: waist; blood pressure; total, high-density lipoprotein or low-density lipoprotein-cholesterol; triglycerides; fasting glucose; homeostasis model assessment; high-sensitivity C-reactive protein; personal history of cardiovascular, respiratory or metabolic diseases. For each set, prevalence of MHO was assessed for body mass index (BMI); waist or percent body fat. Among obese (BMI 30 kg/m(2)) participants, prevalence of MHO ranged between 3.3 and 32.1% in men and between 11.4 and 43.3% in women according to the criteria used. Using abdominal obesity, prevalence of MHO ranged between 5.7 and 36.7% (men) and 12.2 and 57.5% (women). Using percent body fat led to a prevalence of MHO ranging between 6.4 and 43.1% (men) and 12.0 and 55.5% (women). MHO participants had a lower odd of presenting a family history of type 2 diabetes. After multivariate adjustment, the odds of presenting with MHO decreased with increasing age, whereas no relationship was found with gender, alcohol consumption or tobacco smoking using most sets of criteria. Physical activity was positively related, whereas increased waist was negatively related with BMI-defined MHO. MHO prevalence varies considerably according to the criteria used, underscoring the need for a standard definition of this metabolic entity. Physical activity increases the likelihood of presenting with MHO, and MHO is associated with a lower prevalence of family history of type 2 diabetes.