A Comparative In Vitro and In Vivo Study of Osteogenicity by Using Two Biomaterials and Two Human Mesenchymal Stem Cell Subtypes.

Background: Bone repair induced by stem cells and biomaterials may represent an alternative to autologous bone grafting. Mesenchymal stromal/stem cells (MSCs), easily accessible in every human, are prototypical cells that can be tested, alone or with a biomaterial, for creating new osteoblasts. The aim of this study was to compare the efficiency of two biomaterials-biphasic calcium phosphate (BCP) and bioactive glass (BG)-when loaded with either adult bone marrow mesenchymal stem cells (BMMSCs) or newborn nasal ecto-mesenchymal stem cells (NE-MSCs), the latter being collected for further repair of lip cleft-associated bone loss. Materials and Methods: BMMSCs were collected from two adults and NE-MSCs from two newborn infants. An in vitro study was performed in order to determine the best experimental conditions for adhesion, viability, proliferation and osteoblastic differentiation on BCP or BG granules. Bone-associated morphological changes and gene expression modifications were quantified using histological and molecular techniques. The in vivo study was based on the subcutaneous implantation in nude mice of the biomaterials, loaded or not with one of the two cell types. Eight weeks after, bone formation was assessed using histological and electron microscopy techniques. Results: Both cell types-BMMSC and NE-MSC-display the typical stem cell surface markers-CD73+, CD90+, CD105+, nestin - and exhibit the MSC-associated osteogenic, chondrogenic and adipogenic multipotency. NE-MSCs produce less collagen and alkaline phosphatase than BMMSCs. At the transcript level, NE-MSCs express more abundantly three genes coding for bone sialoprotein, osteocalcin and osteopontin while BMMSCs produce extra copies of RunX2. BMMSCs and NE-MSCs adhere and survive on BCP and BG. In vivo experiments reveal that bone formation is only observed with BMMSCs transplanted on BCP biomaterial. Conclusion: Although belonging to the same superfamily of mesenchymal stem cells, BMMSCs and NE-MSCs exhibit striking differences, in vitro and in vivo. For future clinical applications, the association of BMMSCs with BCP biomaterial seems to be the most promising.

'Postnatal growth during the first five years of life in SGA and AGA neonates with reduced fetal growth'.

BACKGROUND: Even though a lot of research has been done on postnatal growth and the occurrence of catch-up growth in small-for-gestational age (SGA) neonates, this phenomenon has not been studied well in appropriate-for-gestational age (AGA) neonates. Postnatal catch-up growth may also occur in AGA neonates indicating a compensatory mechanism for undiagnosed intrauterine growth restriction, especially in AGA neonates with reduced fetal growth velocity. AIMS: To describe postnatal growth during the first 5 years of life in SGA and AGA neonates and evaluating the role of fetal growth velocity in catch-up growth. STUDY DESIGN: Retrospective study in a Dutch tertiary hospital. SUBJECTS: 740 singleton neonates, without congenital anomalies, with ultrasound fetal growth data from 20 weeks and 32 weeks of pregnancy. OUTCOME MEASURES: Postnatal growth measurements of height (cm) and weight (kg) from birth until five years of age. Postnatal catch-up growth defined as difference (delta) in both height and weight between 4 weeks and 3 years of age. RESULTS AND CONCLUSIONS: SGA neonates had a significantly lower height and weight compared to the AGA group for all available measurement moments till 3 years. The catch-up growth between the SGA and AGA groups from 4 weeks up to 3 years after birth was not different between the two groups. However, neonates with reduced fetal growth velocity had a significantly higher risk for catch-up growth in height during the first 3 years after birth. This suggests a role for fetal growth velocity measurement in predicting fetal and subsequent postnatal growth potential.

Social functioning and subclinical psychosis in adolescence: a longitudinal general adolescent population study.

OBJECTIVES: To investigate the longitudinal relationship between subclinical psychotic symptoms and social functioning in a representative general population sample of adolescents. METHOD: Data were derived from a routine general health screening of 1909 adolescents in a circumscribed region. Baseline measurement was in the second grade of secondary school (T0), and follow-up occurred approximately 2 years later (T1). Social functioning and subclinical psychotic symptoms of hallucinations and delusions were assessed at both time points. RESULTS: Baseline (T0) social problems preceded follow-up (T1) subclinical delusions, but not T1 subclinical hallucinations. Similarly, T0 delusions preceded social problems at T1, but T0 hallucinations did not. CONCLUSION: This longitudinal general population study demonstrated a bidirectional association between social problems and delusions, but found no link between social problems and hallucinations. This may reflect a downward negative spiral where delusional thoughts and social problems reinforce each other.

Strength exercises during physical education classes in secondary schools improve body composition: a cluster randomized controlled trial.

BACKGROUND: Metabolic health in people with obesity is determined by body composition. In this study, we examined the influence of a combined strength exercise and motivational programme -embedded in the school curriculum- on adolescents body composition and daily physical activity. METHODS: A total of 695 adolescents (11-15y) from nine Dutch secondary schools participated in a one year cluster randomised controlled trial (RCT). In the intervention schools, physical education teachers were instructed to spend 15-30 min of all physical education lessons (2× per week) on strength exercises. Monthly motivational lessons were given to stimulate students to be more physically active. Control schools followed their usual curriculum. The primary outcome measure was body composition assessed by the deuterium dilution technique. Daily physical activity and sedentary behaviour measured by accelerometry served as a secondary outcome. RESULTS: After 1 year, a 1.6% fat mass difference was found in favour of the intervention group (p = .007). This reflected a 0.9 kg difference in fat free mass (intervention>control; p = .041) and 0.7 kg difference in fat mass (intervention

[Missed lessons, missed opportunities: a role for public health services in medical absenteeism in young people]. / Gemiste lessen, gemiste kansen.

Young people who often miss school for health reasons are not only missing education, but also the daily routine of school, and social intercourse with their classmates. Medical absenteeism among students merits greater attention. For a number of years, in various regions in the Netherlands, students with extensive medical absenteeism have been invited to see a youth healthcare specialist. The MASS intervention (Medical Advice of Students reported Sick; in Dutch: Medische Advisering van de Ziekgemelde Leerling, abbreviated as M@ZL) has been developed by the West Brabant Regional Public Health Service together with secondary schools to address school absenteeism due to reporting sick. In this paper we discuss the MASS intervention and explain why attention should be paid by public health services to the problem of school absenteeism, especially absenteeism on health grounds.

Olfactory stem cells reveal MOCOS as a new player in autism spectrum disorders.

With an onset under the age of 3 years, autism spectrum disorders (ASDs) are now understood as diseases arising from pre- and/or early postnatal brain developmental anomalies and/or early brain insults. To unveil the molecular mechanisms taking place during the misshaping of the developing brain, we chose to study cells that are representative of the very early stages of ontogenesis, namely stem cells. Here we report on MOlybdenum COfactor Sulfurase (MOCOS), an enzyme involved in purine metabolism, as a newly identified player in ASD. We found in adult nasal olfactory stem cells of 11 adults with ASD that MOCOS is downregulated in most of them when compared with 11 age- and gender-matched control adults without any neuropsychiatric disorders. Genetic approaches using in vivo and in vitro engineered models converge to indicate that altered expression of MOCOS results in neurotransmission and synaptic defects. Furthermore, we found that MOCOS misexpression induces increased oxidative-stress sensitivity. Our results demonstrate that altered MOCOS expression is likely to have an impact on neurodevelopment and neurotransmission, and may explain comorbid conditions, including gastrointestinal disorders. We anticipate our discovery to be a fresh starting point for the study on the roles of MOCOS in brain development and its functional implications in ASD clinical symptoms. Moreover, our study suggests the possible development of new diagnostic tests based on MOCOS expression, and paves the way for drug screening targeting MOCOS and/or the purine metabolism to ultimately develop novel treatments in ASD.

Stabilizing prevalence trends of eczema, asthma and rhinoconjunctivitis in Dutch schoolchildren (2001-2010).

In contrast to many countries, a decrease in childhood wheeze prevalence was previously reported for the Netherlands. In repeated cross-sectional surveys in 2001, 2005 and 2010, we investigated whether this trend continued, and additionally examined prevalence trends of eczema, asthma and rhinoconjunctivitis among 8- to 11-year-old schoolchildren eligible for a routine physical examination. Overall, ~90% participated (mean age: 8.8 years in 2001 and 10.5 years in 2005 and 2010). Eczema, wheeze and asthma prevalence did not change significantly between 2001 and 2010, but rhinoconjunctivitis prevalence increased from 8.4% in 2001 to 12.3% in both 2005 and 2010 (Ptrend < 0.01). In conclusion, after a decrease in wheeze prevalence among Dutch schoolchildren between 1989 and 2001, no further decrease was observed until 2010. Similarly, the prevalence of eczema and asthma remained stable, but rhinoconjunctivitis prevalence increased between 2001 and 2010. The latter may be an effect of older age and not a true increase over time.

'Vitamin D and cognition in older adults': updated international recommendations.

BACKGROUND: Hypovitaminosis D, a condition that is highly prevalent in older adults aged 65 years and above, is associated with brain changes and dementia. Given the rapidly accumulating and complex contribution of the literature in the field of vitamin D and cognition, clear guidance is needed for researchers and clinicians. METHODS: International experts met at an invitational summit on 'Vitamin D and Cognition in Older Adults'. Based on previous reports and expert opinion, the task force focused on key questions relating to the role of vitamin D in Alzheimer's disease and related disorders. Each question was discussed and voted using a Delphi-like approach. RESULTS: The experts reached an agreement that hypovitaminosis D increases the risk of cognitive decline and dementia in older adults and may alter the clinical presentation as a consequence of related comorbidities; however, at present, vitamin D level should not be used as a diagnostic or prognostic biomarker of Alzheimer's disease due to lack of specificity and insufficient evidence. This population should be screened for hypovitaminosis D because of its high prevalence and should receive supplementation, if necessary; but this advice was not specific to cognition. During the debate, the possibility of 'critical periods' during which vitamin D may have its greatest impact on the brain was addressed; whether hypovitaminosis D influences cognition actively through deleterious effects and/or passively by loss of neuroprotection was also considered. CONCLUSIONS: The international task force agreed on five overarching principles related to vitamin D and cognition in older adults. Several areas of uncertainty remain, and it will be necessary to revise the proposed recommendations as new findings become available.

Vitamin D3 improves respiratory adjustment to fatigue and H-reflex responses in paraplegic adult rats.

We previously demonstrated that vitamin D2 (ergocalciferol) triggers axon regeneration in a rat model of peripheral nerve transection. In order to confirm the regenerative potential of this neuroactive steroid, we performed a study in which vitamin D3 (cholecalciferol) was delivered at various doses to paralytic rats. After spinal cord compression at the T10 level, rats were given orally either vehicle or vitamin D3 at the dose of 50 IU/kg/day or 200 IU/kg/day. Three months later, M and H-waves were recorded from rat Tibialis anterior muscle in order to quantify the maximal H-reflex (H(max)) amplitude. We also monitored the ventilatory frequency during an electrically induced muscle fatigue known to elicit the muscle metaboreflex and an increase in respiratory rate. Spinal cords were then collected, fixed and immunostained with an anti-neurofilament antibody. We show here that vitamin D-treated animals display an increased number of axons within the lesion site. In addition, rats supplemented with vitamin D3 at the dose of 200 IU/kg/day exhibit (i) an improved breathing when hindlimb was electrically stimulated; (ii) an H-reflex depression similar to control animals and (iii) an increased number of axons within the lesion and in the distal area. Our data confirm that vitamin D is a potent molecule that can be used for improving neuromuscular adaptive mechanisms and H-reflex responses.

Nasal OEC transplantation promotes respiratory recovery in a subchronic rat model of cervical spinal cord contusion.

Engraftment of nasal olfactory ensheathing cells (OEC) is considered as a promising therapeutic strategy for spinal cord repair and one clinical trial has already been initiated. However, while the vast majority of fundamental studies were focused on the recovery of locomotor function, the efficiency of this cellular tool for repairing respiratory motor dysfunction, which affects more than half of paraplegic/tetraplegic patients, remains unknown. Using a rat model that mimics the mechanisms encountered after a cervical contusion that induces a persistent hemi-diaphragmatic paralysis, we assessed the therapeutic efficiency of a delayed transplantation (2 weeks post-contusion) of nasal OECs within the injured spinal cord. Functional recovery was quantified with respiratory behavior tests, diaphragmatic electromyography and neuro-electrophysiological recording of the phrenic motoneurons while axogenesis was evaluated using immunohistochemistry. We show that 3 months post-transplantation, nasal OECs improve i) breathing movements, ii) activities of the ipsilateral diaphragm and corresponding phrenic nerve, and iii) axonal sprouting in the injury site. We also demonstrate that this functional partial recovery is mediated by the restoration of ipsilateral supraspinal command. Our study brings further evidence that olfactory ensheathing cells could have clinical application especially in tetraplegic patients with impaired breathing movements. This article is part of a Special Issue entitled: Understanding olfactory ensheathing glia and their prospect for nervous system repair.

Developmental changes in semantic verbal fluency: analyses of word productivity as a function of time, clustering, and switching.

We investigated age-related improvement in semantic category verbal fluency (VF) in 309 Dutch schoolchildren attending first to ninth grade. Quantitative analyses of number of correct responses as a function of time as well as qualitative analyses of clustering and switching were conducted. Overall, Dutch VF task performance, i.e., number of correct responses over 60 seconds, was not established before mid-adolescence. This is in line with previously published studies, using VF number of correct responses over 60 seconds as the main outcome measure and examining VF task performance across other cultures and languages (e.g., Italian, French, Hebrew). Next, mean cluster size, a measure of lexico-semantic knowledge, was not established until at least grade 3. In contrast, performance on the VF outcome measures "number of switches/clusters" was established at least 4 years later. Qualitative and quantitative Design Fluency (DF) outcome measures support the notion that the numbers of switches/clusters are valid measures of higher order cognitive functions, such as strategy use and cognitive flexibility. In line of this, VF number of correct responses during 16-60 seconds, a measure of controlled information processing, is established at least 2 years later (i.e., grades 7-8) than number of correct responses during the first 15 seconds time slide, a measure of automatic processing. Finally, environment, i.e., the level of parental education, primarily affected automatic and lexico-semantic knowledge. No effects of sex on VF performance were found. These data suggest that the alternative scoring methods of VF tasks can be used to acquire knowledge on development of lower and higher order cognitive functions in healthy children and the influence of the environment on it.

Season of birth and not vitamin D receptor promoter polymorphisms is a risk factor for multiple sclerosis.

Both genetic and environmental factors contribute to multiple sclerosis, the most common neurodegenerative disorder with onset in young adults. The objective of the current study is, based on the hypothesis that environmentally predisposed individuals are at risk for multiple sclerosis, to investigate whether they also carry genetic variants within the vitamin D machinery. Using medical files and DNA samples from 583 trios (a patient and both parents) of the French Multiple Sclerosis Genetics Group as well as data from the French Statistics Bureau, we aimed to assess whether: (1) a seasonality of birth was observed in French multiple sclerosis patients; (2) three single nucleotide polymorphisms within the promoter region of the vitamin D receptor were associated with multiple sclerosis susceptibility; and (3) the combination of a high risk month of birth and vitamin D receptor polymorphisms were correlated to multiple sclerosis incidence. We observed a significantly reduced number of individuals born in November who were later diagnosed as multiple sclerosis patients. However, we found no association between the three studied vitamin D receptor polymorphisms and multiple sclerosis. In conclusion, our data suggest that high levels of vitamin D during the third trimester of pregnancy could be a protective factor for multiple sclerosis.

Developmental vitamin D deficiency causes abnormal brain development.

There is now clear evidence that vitamin D is involved in brain development. Our group is interested in environmental factors that shape brain development and how this may be relevant to neuropsychiatric diseases including schizophrenia. The origins of schizophrenia are considered developmental. We hypothesised that developmental vitamin D (DVD) deficiency may be the plausible neurobiological explanation for several important epidemiological correlates of schizophrenia namely: (1) the excess winter/spring birth rate, (2) increased incidence of the disease in 2nd generation Afro-Caribbean migrants and (3) increased urban birth rate. Moreover we have published two pieces of direct epidemiological support for this hypothesis in patients. In order to establish the "Biological Plausibility" of this hypothesis we have developed an animal model to study the effect of DVD deficiency on brain development. We do this by removing vitamin D from the diet of female rats prior to breeding. At birth we return all dams to a vitamin D containing diet. Using this procedure we impose a transient, gestational vitamin D deficiency, while maintaining normal calcium levels throughout. The brains of offspring from DVD-deficient dams are characterised by (1) a mild distortion in brain shape, (2) increased lateral ventricle volumes, (3) reduced differentiation and (4) diminished expression of neurotrophic factors. As adults, the alterations in ventricular volume persist and alterations in brain gene and protein expression emerge. Adult DVD-deficient rats also display behavioural sensitivity to agents that induce psychosis (the NMDA antagonist MK-801) and have impairments in attentional processing. In this review we summarise the literature addressing the function of vitamin D on neuronal and non-neuronal cells as well as in vivo results from DVD-deficient animals. Our conclusions from these data are that vitamin D is a plausible biological risk factor for neuropsychiatric disorders and that vitamin D acts as a neurosteroid with direct effects on brain development.

Vitamin D, a neuro-immunomodulator: implications for neurodegenerative and autoimmune diseases.

It has been known for more than 20 years that vitamin D exerts marked effects on immune and neural cells. These non-classical actions of vitamin D have recently gained a renewed attention since it has been shown that diminished levels of vitamin D induce immune-mediated symptoms in animal models of autoimmune diseases and is a risk factor for various brain diseases. For example, it has been demonstrated that vitamin D (i) modulates the production of several neurotrophins, (ii) up-regulates Interleukin-4 and (iii) inhibits the differentiation and survival of dendritic cells, resulting in impaired allo-reactive T cell activation. Not surprisingly, vitamin D has been found to be a strong candidate risk-modifying factor for Multiple Sclerosis (MS), the most prevalent neurological and inflammatory disease in the young adult population. Vitamin D is a seco-steroid hormone, produced photochemically in the animal epidermis. The action of ultraviolet light (UVB) on 7-dehydrocholesterol results in the production of pre-vitamin D which, after thermo-conversion and two separate hydroxylations, gives rise to the active 1,25-dihydroxyvitamin D. Vitamin D acts through two types of receptors: (i) the vitamin D receptor (VDR), a member of the steroid/thyroid hormone superfamily of transcription factors, and (ii) the MARRS (membrane associated, rapid response steroid binding) receptor, also known as Erp57/Grp58. In this article, we review some of the mechanisms that may underlie the role of vitamin D in various brain diseases. We then assess how vitamin D imbalance may lay the foundation for a range of adult disorders, including brain pathologies (Parkinson's disease, epilepsy, depression) and immune-mediated disorders (rheumatoid arthritis, type I diabetes mellitus, systemic lupus erythematosus or inflammatory bowel diseases). Multidisciplinary scientific collaborations are now required to fully appreciate the complex role of vitamin D in mammal metabolism.

Autologous olfactory ensheathing cell transplantation in human paraplegia: a 3-year clinical trial.

Olfactory ensheathing cells show promise in preclinical animal models as a cell transplantation therapy for repair of the injured spinal cord. This is a report of a clinical trial of autologous transplantation of olfactory ensheathing cells into the spinal cord in six patients with complete, thoracic paraplegia. We previously reported on the methods of surgery and transplantation and the safety aspects of the trial 1 year after transplantation. Here we address the overall design of the trial and the safety of the procedure, assessed during a period of 3 years following the transplantation surgery. All patients were assessed at entry into the trial and regularly during the period of the trial. Clinical assessments included medical, psychosocial, radiological and neurological, as well as specialized tests of neurological and functional deficits (standard American Spinal Injury Association and Functional Independence Measure assessments). Quantitative test included neurophysiological tests of sensory and motor function below the level of injury. The trial was a Phase I/IIa design whose main aim was to test the feasibility and safety of transplantation of autologous olfactory ensheathing cells into the injured spinal cord in human paraplegia. The design included a control group who did not receive surgery, otherwise closely matched to the transplant recipient group. This group acted as a control for the assessors, who were blind to the treatment status of the patients. The control group also provided the opportunity for preliminary assessment of the efficacy of the transplantation. There were no adverse findings 3 years after autologous transplantation of olfactory ensheathing cells into spinal cords injured at least 2 years prior to transplantation. The magnetic resonance images (MRIs) at 3 years showed no change from preoperative MRIs or intervening MRIs at 1 and 2 years, with no evidence of any tumour of introduced cells and no development of post-traumatic syringomyelia or other adverse radiological findings. There were no significant functional changes in any patients and no neuropathic pain. In one transplant recipient, there was an improvement over 3 segments in light touch and pin prick sensitivity bilaterally, anteriorly and posteriorly. We conclude that transplantation of autologous olfactory ensheathing cells into the injured spinal cord is feasible and is safe up to 3 years of post-implantation, however, this conclusion should be considered preliminary because of the small number of trial patients.

Neurotrophin expression in the adult olfactory epithelium.

Published reports of neurotrophin expression in the olfactory system are incomplete because of missing data and conflicting results. Previous studies used a variety of fixation procedures and antibodies on different species and different ages. The aim of the present study was to examine expression of neurotrophins and their receptors using optimized methodologies: five methods of fixation, multiple antibodies, a variety of immunochemical protocols, and RT-PCR. We show here that (i) transcripts for all neurotrophins and their receptors are found in the adult olfactory epithelium; (ii) all neurotrophins are expressed in the supporting cells and the neuronal layers of the undisturbed adult olfactory epithelium while NT4 is found additionally in the horizontal basal cells; (iii) neurotrophin immunoreactivity required a fixative that included parabenzoquinone (not used in previous studies of olfactory tissue); (iv) TrkB and TrkC are restricted to the globose basal cell and neuron layers while TrkA is found in the horizontal basal cells and in the supporting cells where it co-localizes with the low affinity receptor for NGF (p75NTR). These findings confirm that neurotrophins are produced within the olfactory epithelium, suggesting autocrine and paracrine regulation of olfactory neurogenesis.

[Current cell therapy strategies for repairing the central nervous system]. / Réparation du système nerveux central: les stratégies actuelles de thérapie cellulaire.

One of the chief contemporary goals of neurologists and neuroscientists is to find a way to overcome the debilitating effects of brain diseases, especially neurodegenerative diseases. Since very few molecules have been found to be efficient in curing the patients and even halting the progression of the symptoms, cell therapy is now seen as an attractive alternative. Two therapeutic strategies are currently under investigation: i) the "substitution" strategy, based on grafts of cells capable of differentiating in the appropriate cells and restoring lost functions and ii) the "neuroprotective" or "conservative" strategy aiming to increase the resistance of spared cells to the toxicity of their environment and to reinforce the body's own mechanisms of healing. Twenty years ago, foetal neuroblasts were the first cells to be transplanted in the brains of patients with Parkinson's or Huntington disease. A phase II clinical trial is presently conducted in France for the latter disorder. However, the numerous ethical and technical issues raised by the use of embryonic and foetal cells have directed the focus of clinicians and researchers towards substitute cell types. In this review, we summarise the main findings of the most recent basic studies and clinical trials based on: i) the grafting of surrogate adult cells such as bone marrow mesenchymal stem cells and olfactory ensheathing cells; ii) the potential therapeutic applications of neuropoiesis - the persistent neurogenesis in the brain - as a source for tissue engraftment and as self-repair by a person's own indigenous population of pluripotent cells and iii) immune-based therapy (autologous activated macrophages and T cell vaccination) as well as administration of immunomodulatory molecules. Unexpectedly, it has been found that undifferentiated adult stem cells can display immune-like functions when they home in on an inflamed brain area while immune cells and immunosuppressors can improve functional and morphological recovery when administered within the appropriate time-window. On the one hand, outcomes from substitution therapy trials are encouraging. They pave the way for an enlarged use of various adult cell types for various neurological disorders. On the other hand, clinical benefits of the neuroprotective therapy, still under close scrutiny, look rather promising. It is likely that, in a close future, the two strategies will be combined in order to efficiently repair the pathological, the damaged or the senescent brain.

Developmental vitamin D deficiency alters the expression of genes encoding mitochondrial, cytoskeletal and synaptic proteins in the adult rat brain.

Epidemiology has highlighted the links between season of birth, latitude and the prevalence of brain disorders such as multiple sclerosis and schizophrenia. In line with these data, we have hypothesized that "imprinting" with low prenatal vitamin D could contribute to the risk of these two brain disorders. Previously, we have shown that transient developmental hypovitaminosis D induces permanent changes in adult nervous system. The aim of this study was to examine the impact of prenatal hypovitaminosis D on gene expression in the adult rat brain. Vitamin D deficient female rats were mated with undeprived males and the offspring were fed with a control diet after birth. At Week 10, gene expression in the progeny's brain was compared with control animals using Affymetrix gene microarrays. Prenatal hypovitaminosis D causes a dramatic dysregulation of several biological pathways including oxidative phosphorylation, redox balance, cytoskeleton maintenance, calcium homeostasis, chaperoning, post-translational modifications, synaptic plasticity and neurotransmission. A computational analysis of these data suggests that impaired synaptic network may be a consequence of mitochondrial dysfunction. Since disruptions of mitochondrial metabolism have been associated with both multiple sclerosis and schizophrenia, developmental vitamin D deficiency may be a heuristic animal model for the study of these two brain diseases.