A nutrigenomics approach for the study of anti-aging interventions: olive oil phenols and the modulation of gene and microRNA expression profiles in mouse brain.

PURPOSE: Middle-aged C57Bl/6J mice fed for 6 months with extra-virgin olive oil rich in phenols (H-EVOO, phenol dose/day: 6 mg/kg) showed cognitive and motor improvement compared to controls fed the same olive oil deprived of phenolics (L-EVOO). The aim of the present study was to evaluate whether these behavioral modifications were associated with changes in gene and miRNA expression in the brain. METHODS: Two brain areas involved in cognitive and motor processes were chosen: cortex and cerebellum. Gene and miRNA profiling were analyzed by microarray and correlated with performance in behavioral tests. RESULTS: After 6 months, most of the gene expression changes were restricted to the cerebral cortex. The genes modulated by aging were mainly down-regulated, and the treatment with H-EVOO was associated with a significant up-regulation of genes compared to L-EVOO. Among those, we found genes previously associated with synaptic plasticity and with motor and cognitive behavior, such as Notch1, BMPs, NGFR, GLP1R and CRTC3. The agrin pathway was also significantly modulated. miRNAs were mostly up-regulated in old L-EVOO animals compared to young. However, H-EVOO-fed mice cortex displayed miRNA expression profiles similar to those observed in young mice. Sixty-three miRNAs, out of 1203 analyzed, were significantly down-regulated compared to the L-EVOO group; among them, we found miRNAs whose predicted target genes were up-regulated by the treatment, such as mir-484, mir-27, mir-137, mir-30, mir-34 and mir-124. CONCLUSIONS: We are among the first to report that a dietary intervention starting from middle age with food rich in phenols can modulate at the central level the expression of genes and miRNAs involved in neuronal function and synaptic plasticity, along with cognitive, motor and emotional behavior.

[Psychomotor education and speech therapy when weaning a child off artificial feeding]. / Psychomotricité et orthophonie lors du sevrage d'une nutrition artificielle chez l'enfant.

To support children and their families with weaning off artificial nutrition, a psychomotor therapist and speech therapist from the 'Pierre Robin syndrome and congenital sucking-swallowing disorders' specialist rare disease centre at Necker-Enfant Malades hospital in Paris, have set up a joint consultation, as a complement to medical consultations. This programme shows how speech therapy and psychomotor education can complement each other in order to help children and their parents during this difficult period.

Oral administration of curcumin relieves behavioral alterations and oxidative stress in the frontal cortex, hippocampus, and striatum of ovariectomized Wistar rats.

Menopause occurs gradually and is characterized by increased susceptibility to developing mood disorders. Several studies have suggested treatments based on the antioxidant properties of vitamins and herbal compounds as an alternative to hormone replacement therapies, with few or none reporting toxicity. The present study was performed to explore the effects of curcumin oral supplementation on anxiety-like behavior and oxidative stress parameters in different central nervous system (CNS) areas of ovariectomized (OVX) rats. Female Wistar rats were randomly divided into either sham-operated or OVX groups. Sham-operated group (n=8) and an OVX group (n=11) were treated with vehicle, and the other two OVX groups received curcumin at 50 or 100mg/kg/day doses (n=8/group). Elevated plus maze (EPM) test was performed on the 28th day of treatment. On the 30th day, animals were killed and the dissected brain regions were removed and stored at-80°C until analysis. Ovariectomy induced deficit in the locomotor activity and increased anxiety-like behavior. Moreover, OVX rats showed increased lipid oxidized in the frontal cortex and striatum, increased hippocampal and striatal carbonylated protein level, and decreased striatal thiol content of non-protein fraction indicative of a glutathione (GSH) pool. Curcumin oral treatment for 30days reduced oxidative stress in the CNS areas as well as the behavior alterations resulting from ovariectomy. Curcumin supplementation attenuated most of these parameters to sham comparable values, suggesting that curcumin could have positive effects against anxiety-like disturbances and brain oxidative damage due to hormone deprivation.

Prenatal exposure to methyl mercury from fish consumption and polyunsaturated fatty acids: associations with child development at 20 mo of age in an observational study in the Republic of Seychelles.

BACKGROUND: Fish is a rich source of n-3 polyunsaturated fatty acids (PUFAs) but also contains the neurotoxicant methyl mercury (MeHg). PUFAs may modify the relation between prenatal MeHg exposure and child development either directly by enhancing neurodevelopment or indirectly through the inflammatory milieu. OBJECTIVE: The objective was to investigate the associations of prenatal MeHg exposure and maternal PUFA status with child development at 20 mo of age. DESIGN: The Seychelles Child Development Study Nutrition Cohort 2 is an observational study in the Republic of Seychelles, a high-fish-eating population. Mothers were enrolled during pregnancy and their children evaluated at 20 mo of age by using the Bayley Scales of Infant Development II (BSID-II), the MacArthur Bates Communicative Development Inventories (CDI), and the Infant Behavior Questionnaire-Revised. There were 1265 mother-child pairs with complete data. RESULTS: Prenatal MeHg exposure had no direct associations with neurodevelopmental outcomes. Significant interactions were found between MeHg and PUFAs on the Psychomotor Developmental Index (PDI) of the BSID-II. Increasing MeHg was associated with lower PDI but only in children of mothers with higher n-6/n-3. Among mothers with higher n-3 PUFAs, increasing MeHg was associated with improved PDI. Higher maternal docosahexaenoic acid (DHA) was associated with improved CDI total gestures (language development) but was significantly adversely associated with the Mental Development Index (MDI), both with and without MeHg adjustment. Higher n-6:n-3 ratios were associated with poorer scores on all 3 CDI outcomes. CONCLUSIONS: We found no overall adverse association between prenatal MeHg exposure and neurodevelopmental outcomes. However, maternal PUFA status as a putative marker of the inflammatory milieu appeared to modify the associations of prenatal MeHg exposure with the PDI. Increasing DHA status was positively associated with language development yet negatively associated with the MDI. These findings may indicate the existence of an optimal DHA balance with respect to arachidonic acid for different aspects of neurodevelopment.

Non-invasive brain stimulation in neurological diseases.

Non-invasive brain stimulation has shown its potential to modulate brain plasticity in humans. Endeavour has been made to utilize brain stimulation in neurological diseases to enhance adaptive processes and prevent potential maladaptive ones. In stroke for instance both sensorimotor and higher cognitive impairment, such as aphasia and neglect, has been addressed to facilitate functional recovery. In Parkinson's disease, brain stimulation has been evaluated to improve motor and non-motor symptoms. In the present review we provide an update of the field of transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) as non-invasive brain stimulation techniques to improve motor and higher cognitive functions in patients suffering from stroke and Parkinson's disease. Rather than attempting to be comprehensive in regard of the reviewed scientific field, this article may be considered as a present day's framework of the application of non-invasive brain stimulation on selected examples of common neurological diseases. At the end we will briefly discuss open controversies and future directions of the field which has to be addressed in upcoming studies. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

The mGlu5 positive allosteric modulator LSN2463359 differentially modulates motor, instrumental and cognitive effects of NMDA receptor antagonists in the rat.

Metabotropic glutamate 5 (mGlu5) receptors are known to functionally interact with N-methyl-d-aspartate (NMDA) receptors at both neuronal and behavioural levels, in a manner that may be of relevance to the treatment of schizophrenia. We have previously described a novel mGlu5 positive allosteric modulator (PAM), LSN2463359 and provided evidence of its ability to attenuate aspects of the behavioural response to administration of the competitive NMDA receptor antagonist, SDZ 220,581. In addition, LSN2463359 was found to selectively attenuate reversal learning deficits observed in the neurodevelopmental MAM E17 model but not in the acute phencyclidine (PCP) model. In the present study, the interactions between this mGlu5 PAM and the NMDA receptor were explored further by assessing the effects of LSN2463359 against some of the motor, instrumental and cognitive effects induced by the non-competitive NMDA receptor antagonists PCP and MK-801, the competitive NMDA receptor antagonist SDZ 220,581 and the GluN2B selective NMDA receptor antagonist, Ro 63-1908. LSN2463359 had either no or minor impact on locomotor hyperactivity induced by either PCP or SDZ 220,581. However, in rats lever pressing for food rewards under a variable interval 30s schedule of instrumental responding, the drug clearly attenuated not only the suppression of response rate induced by SDZ 220,581 but also the stimulation of response rate induced by Ro 63-1908. In contrast, LSN2463359 failed to alter both of the instrumental effects induced by the open channel blockers PCP and MK-801. In addition, although PCP and SDZ 220,581 induced similar deficits in a discrimination and reversal learning task, LSN2463359 was again only able to reverse the deficit induced by SDZ 220,581. The results indicate that the interactions between mGlu5 and NMDA receptors are dependent on both the mechanism of the blockade of the receptor and the behavioural domain under investigation. Our work has implications for the preclinical use of NMDA receptor antagonists in the prediction of potential therapeutic efficacy in the search for novel treatments for schizophrenia. Positive allosteric modulators of the mGlu5 receptor certainly question the predictive validity of such approaches. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

Rich micronutrient fortification of locally produced infant food does not improve mental and motor development of Zambian infants: a randomised controlled trial.

It is uncertain whether multiple micronutrients benefit the mental and psychomotor development of young children in developing countries. We conducted a randomised double-blind controlled trial to evaluate the effect of a richly micronutrient-fortified v. a basal fortified porridge on mental and psychomotor development in Zambian infants. Infants (n 743) were randomised at age 6 months to receive either the richly fortified or the basal fortified infant food and were followed up until 18 months of age. All the infants were evaluated monthly for achievement of a series of developmental milestones. The Bayley scales of infant development II were administered to a subsample of 502 infants at 6, 12 and 18 months. Rich micronutrient fortification had no significant benefit on the following: (a) number of developmental milestones achieved (rate ratio at 12 months = 1·00; 95 % CI 0·96, 1·05; P = 0·81, adjusted for sex, socio-economic status and maternal education, with similar results at 15 and 18 months); (b) ages of walking unsupported (hazard ratio (HR) 1·04; 95 % CI 0·88, 1·24; P = 0·63, adjusted for the above covariates) and of speaking three or four clear words (HR 1·01; 95 % CI 0·84, 1·20; P = 0·94, adjusted for the above covariates); (c) mental development index (MDI) and psychomotor development index (PDI) of the Bayley scales (scores difference adjusted for baseline scores, age at the assessment, sex, socio-economic status, maternal education, language, age and HIV status: MDI 0·3 (95 % CI - 0·5, 1·1), P = 0·43; PDI - 0·1 (95 % CI - 0·9, 0·7), P = 0·78). In conclusion, the results do not support the hypothesis that rich micronutrient fortification improves Zambian infants' mental and motor development.

Acetyl-L-carnitine and α-lipoic acid affect rotenone-induced damage in nigral dopaminergic neurons of rat brain, implication for Parkinson's disease therapy.

Although the mechanisms of neurodegeneration in Parkinson's disease are not fully understood, mitochondrial dysfunction, oxidative stress and environmental toxins may be involved. The current research was directed to investigate the protective role of two bioenergetic antioxidants, acetyl-L-carnitine and α-lipoic acid, in rotenone-parkinsonian rats. Ninety six male rats were divided into five groups. Group I is the vehicle-injected group, group II is the disease control group and was injected with six doses of rotenone (1.5 mg/kg/48 h, s.c.). Groups III, IV and V received rotenone in addition to acetyl-L-carnitine (100 mg/kg/day, p.o.), α-lipoic acid (50 mg/kg/day, p.o.) or their combination, respectively. Results showed that rotenone-treated rats exhibited bradykinesia and motor impairment in the open-field and square bridge tests. In addition, ATP level was decreased whereas lipid peroxides and protein carbonyls increased in the striata of rotenone-treated rats as compared to vehicle-treated rats. Treatment with acetyl-L-carnitine or α-lipoic acid improved the motor performance and reduced the level of lipid peroxides in rat brains as compared to rotenone group. Further, ATP production was enhanced along with acetyl-L-carnitine treatments (p≤0.05). Taken together, our study reinforces the view that acetyl-L-carnitine and α-lipoic acid are promising candidates for neuroprotection in Parkinson's disease.

Prevención del retraso psicomotor causado por déficit de yodo en la infancia / No disponible

El yodo es un elemento esencial para el desarrollo humano; interviene fundamentalmenteen la síntesis de hormonas tiroideas, tan cruciales en el desarrollo neurológico. La carenciade yodo afecta al menos a la tercera parte de la humanidad y es responsable de cuadrosde bocio, cretinismo así como de pérdidas fetales y de aumentar la mortalidad infantil.La carencia de yodo cuando es moderada puede ser responsable de trastornos más leves deldesarrollo neurológico con un menor cociente intelectual y, posiblemente, de trastorno dedéficit de atención.En España y en otros países desarrollados existen zonas o grupos poblacionales expuestosa carencias moderadas de yodo. Una forma de evaluar la carencia en yodo de una comunidades ver el porcentaje de determinaciones neonatales de TSH > 5 mU/l. Se ha podidocomprobar también en nuestro país que durante el embarazo las necesidades de yodo aumentany las yodurias descienden por debajo de lo que la OMS considera el umbral mínimopara la carencia de yodo.A pesar de todo, todavía no hay pruebas concluyentes que demuestren que el suplementoprecoz con yodo durante el embarazo mejore el desarrollo neurológico de los niños alargo plazo.Se recomienda la profilaxis con sal yodada para toda la población y conocer las cifrasde TSH procedentes del cribado metabólico neonatal. Se debe estudiar más la existencia decarencias yodadas durante el embarazo y si los suplementos con yodo mejoran el desarrolloneurológico de los niños a largo plazo

Iodine is one of the main elements for human development; it intervenes in the synthesisof thyroid hormones and neurodevelopment. Iodine deficiency affects to one thirdof world population. Iodine deficiency is responsible of disorders as goitre and infant cretinism,and it raises child mortality. Mild iodine deficiency can also be responsible ofmild neurologic developmental disorders as borderline cognitive skills or attention deficitand hyperactivity disorders. In Spain there are communities with mild iodine deficiency.One of the methods to evaluate the community iodine deficit is to know de ratio of theneonatal TSH > 5 MU/l from neonatal mass screening. During pregnancy yoduria oftendecreases under level of deficiency (defined by OMS). Nowadays there aren’t proofs ofefficacy of iodine supplementation since the beginning of pregnancy in the long termneurodevelopment of the child. Authors recommend iodized salt use for all the populationand to know the value of TSH neonatal screening of each child. It is necessary tostudy the effects of iodine supplementation during pregnancy in the long term neurodevelopmentof the children (AU)

Erythropoietin concentrations and neurodevelopmental outcome in preterm infants.

OBJECTIVE: Erythropoietin therapy is effective in decreasing transfusions to varying degrees in preterm infants. Recent animal studies using erythropoietin doses to achieve serum concentrations > 1000 mU/mL report neuroprotective effects. We evaluated the relationship between erythropoietin concentrations and neurodevelopmental outcome in extremely low birth weight infants. METHODS: Preterm infants who weighed < or = 1000 g at birth were randomly assigned to erythropoietin (400 U/kg 3 times per week) or placebo/control. Therapy was initiated by 4 days after birth and continued through the 35th postmenstrual week. All infants received supplemental parenteral and enteral iron. Peak serum erythropoietin concentrations were obtained every 2 weeks. Follow-up evaluation included anthropometric measurements, Bayley scales of mental and psychomotor development, neurologic examination, and determination of overall neurodevelopmental impairment. Data were collected at 18 to 22 months' corrected age by certified examiners who were masked to the treatment group. Analyses were performed to identify correlations between erythropoietin concentrations and outcomes. RESULTS: Sixteen extremely low birth weight infants were enrolled; 1 infant died at 2 weeks (placebo/control), and 15 had erythropoietin concentrations measured (7 erythropoietin, 8 placebo/control). Peak erythropoietin concentrations were significantly different between groups during the study (erythropoietin: 2027 +/- 1464 mU/mL; placebo/control: 26 +/- 11 mU/mL). Before follow-up, 3 infants died (1 erythropoietin, 2 placebo/control), and 12 were available for follow-up (6 erythropoietin, 6 placebo/control). At 18 to 22 months' follow-up, none of the erythropoietin recipients and 2 of the placebo/control infants had Mental Development Index scores < 70. Erythropoietin recipients had Mental Development Index scores of 96 +/- 11, and placebo/control infants had Mental Development Index scores of 78 +/- 7. Psychomotor Development Index scores were similar between groups (87 +/- 13 vs 80 +/- 7). There were no differences between groups with respect to anthropometric measurements. Two of 6 infants in the erythropoietin group and 4 of 6 infants in the placebo/control group had some form of neurodevelopmental impairment. Posthoc analysis showed that infants with erythropoietin concentrations > or = 500 mU/mL had higher Mental Development Index scores than infants with erythropoietin concentrations < 500 mU/mL. CONCLUSIONS: Erythropoietin concentrations did not correlate with Psychomotor Development Index or overall incidence of neurodevelopmental impairment; however, infants with elevated erythropoietin concentrations had higher Mental Development Index scores than those with lower erythropoietin concentrations. Close follow-up of infants who are enrolled in large, multicenter, high-dose erythropoietin studies is required to determine whether a correlation exists between elevated erythropoietin concentrations and improved neurodevelopmental outcome.

Neurodevelopmental outcome and growth at 18 to 22 months' corrected age in extremely low birth weight infants treated with early erythropoietin and iron.

BACKGROUND: Clinical trials evaluating the use of erythropoietin (Epo) have demonstrated a limited reduction in transfusions; however, long-term developmental follow-up data are scarce. OBJECTIVE: We compared anthropometric measurements, postdischarge events, need for transfusions, and developmental outcomes at 18 to 22 months' corrected age in extremely low birth weight (ELBW) infants treated with early Epo and supplemental iron therapy with that of placebo/control infants treated with supplemental iron alone. METHODS: The National Institute of Child Health and Human Development Neonatal Research Network completed a randomized, controlled trial of early Epo and iron therapy in preterm infants < or =1250 g. A total of 172 ELBW (< or =1000-g birth weight) infants were enrolled (87 Epo and 85 placebo/control). Of the 72 Epo-treated and 70 placebo/control ELBW infants surviving to discharge, follow-up data (growth, development, rehospitalization, transfusions) at 18 to 22 months' corrected age were collected on 51 of 72 Epo-treated infants (71%) and 51 of 70 placebo/controls (73%) by certified examiners masked to the treatment group. Statistical significance was determined using chi2 analysis. RESULTS: There were no significant differences between treatment groups in weight or length or in the percentage of infants weighing <10th percentile either at the time of discharge or at follow-up, and no difference was found in the mean head circumference between groups. A similar percentage of infants in each group was rehospitalized (38% Epo and 35% placebo/control) for similar reasons. There were no differences between groups with respect to the percentage of infants with Bayley-II Mental Developmental Index <70 (34% Epo and 36% placebo/control), blindness (0% Epo and 2% placebo/control), deafness or hearing loss requiring amplification (2% Epo and 2% placebo/control), moderate to severe cerebral palsy (16% Epo and 18% placebo/control) or the percentage of infants with any of the above-described neurodevelopmental impairments (42% Epo and 44% placebo/control). CONCLUSIONS: Treatment of ELBW infants with early Epo and iron does not significantly influence anthropometric measurements, need for rehospitalization, transfusions after discharge, or developmental outcome at 18 to 22 months' corrected age.

Iron supplemented formula milk related to reduction in psychomotor decline in infants from inner city areas: randomised study.

OBJECTIVE: To compare the effect of unmodified cows' milk and iron supplemented formula milk on psychomotor development in infants from inner city areas when used as the main milk source. DESIGN: Double blind, randomised intervention trial. SETTING: Birmingham health centre. SUBJECTS: 100 infants, mean age 7.8 months (range 5.7 to 8.6 months), whose mothers had already elected to use unmodified cows' milk as their infant's milk source. INTERVENTION: Changing to an iron supplemented formula milk from enrolment to 18 months of age, or continuing with unmodified cows' milk. MAIN OUTCOME MEASURES: Developmental assessments using Griffiths scales at enrolment and at 18 and 24 months. RESULTS: 85 participants completed the trial. There were no significant differences in haemoglobin concentration between the two groups at enrolment, but by 18 months of age 33% of the unmodified cows' milk group, but only 2% of the iron supplemented group, were anaemic (P<0.001). The experimental groups had Griffiths general quotient scores that were not significantly different at enrolment, but the scores in both groups declined during the study. By 24 months the decrease in the mean scores in the unmodified cows' milk group was 14.7 whereas the decrease in the mean scores in the iron supplemented group was 9.3 (P<0.02, 95% confidence interval 0.4 to 10.4). Mean subquotient scores were considerably lower in the unmodified cows' milk group at 24 months; significantly so for personal and social scores (P<0.02, 1.2 to 16.8 [corrected]). CONCLUSION: Replacing unmodified cows' milk with an iron supplemented formula milk up to 18 months of age in infants from inner city areas prevents iron deficiency anaemia and reduces the decline in psychomotor development seen in such infants from the second half of the first year.

[Psychomotor management in the rehabilitation of patients with myopathy in infancy. Case studies]. / La practica psicomotoria nella rieducazione del miopatico. Esemplificazione casistica.

The salient features are described of the psychomotor treatment given to two sisters: SA aged 11 yrs 5 months and MGA aged 9 yrs 9 months both affected with aspecific congenital myopathy and under medical treatment since they were 3 months old. These two cases were selected as examples for the following reasons: (1) they may offer the opportunity to highlight what should be the focal objective of all treatment of myopathic children whatever the syndrome involved, namely to ensure that the children retain capacities required for normal social life as long as possible and to help them retain the essential physical capabilities required for everyday life; (2) because the slower course of this type of myopathy permits the gradual implementation of a diversified treatment protocol in the various social contexts (family, school, play groups) in which these patients are able to lead a life whose limitations are scarcely visible for a long time. Experience in the treatment of these two cases confirms that the role of Psychomotor Education in the treatment of myopathy cases is essentially that of teaching the child to be aware of and responsible for its own movements as the disease progresses, while showing it how touse all its available sensomotorial instruments to counteract its muscular inadequacies which progressively damage the child's body image. Psychomotor education also provides the child with the self-assurance it needs in order to retain its autonomy within the framework of a knowledgeable and motivated family.