Low prenatal vitamin D alters morphology, cell density and gene expression in adult rat brain: Correlations with schizophrenia

Statement of the study: Based on data from ecological and analytic epidemiological studies, we have proposed that low prenatal vitamin D is a candidate risk-modifying factor for schizophrenia. Previously, we demonstrated that low prenatal vitamin D adversely affected brain development in neonatal rats (Eyles et al, 2003). Here we examine the impact of both prenatal and early life hypovitaminosis D on various outcomes in the adult rat brain. Methods: Female Sprague-Dawley rats were made vitamin D deficient via the use of a special diet (Dyets CA) and lighting conditions that excluded UVB radiation. Animals were kept under these conditions for 6 weeks then mated with males kept under normal conditions. Vitamin deplete dams were kept under these conditions during pregnancy. Offspring from two test groups were examined. Offspring were either reared with dams repleted with vitamin D at birth or remained under deplete conditions till weaning. Both test groups were weaned under normal vitamin D conditions and remained so till testing at adulthood. We compared the brains of adult offspring kept under both test conditions with animals from control environments. Summary of results: We found a significant persistent dose-related increase in lateral ventricle volume and alterations in anterior cingulate and prefrontal cortical cell densities (consistent with the known prodifferentiation properties of this steroid). In both test groups we observed a reduced expression of NGF as well as a down-regulation of transcripts coding for GABAA alpha 4 receptor and two neuronal structural elements; MAP2 and Neurofilament L. Conclusion: These findings provide further evidence that vitamin D is involved in brain development. An increase in prefrontal cortical cell density, a reduction neuronal structural elements and persistent ventriculomegaly are all common anatomical findings in the brains of patients with schizophrenia. The specific reduction in transcripts for neuronal structural proteins but not GFAP is also in accordance with the proposal that frontal cortical architecture in schizophrenia reflects a reduction in connectivity rather than a reduction in glial processes(Goldman-Rakic and Selemon, 1997). These findings confirm the biological plausibility of early life hypovitaminosis D as a risk factor for schizophrenia.

Developmental vitamin D deficiency alters adult behaviour: An informative animal model of schizophrenia

Background: There is growing evidence that vitamin D is active in the brain but until recently there was a lack of evidence about its role during brain development. Guided by certain features of the epidemiology of schizophrenia, we have explored the role of vitamin D in the developing brain and behaviour using whole animal models. Methods: Sprague-Dawley rats were fed a vitamin D deficient diet (DVD) or control diet 6 weeks prior to mating and housed under UVB-free lighting conditions. On the day of birth all rats were fed a control diet for the remainder of the study. We observed behaviour at two timepoints; on the day of birth to study maternal behaviour, and at 10 weeks of age to study offspring behaviour in adulthood, under baseline and drug induced conditions (MK-801, haloperidol, amphetamine). Results: Prenatal vitamin D deficiency results in subtle alterations in maternal behaviour as well as long lasting effects on the adult offspring, despite a return to normal vitamin D levels during postnatal life. These affects were specific to transient prenatal vitamin D depletion as adult vitamin D depletion, combined prenatal and chronic postnatal vitamin D depletion, or ablation of the vitamin D receptor in mice led to markedly different outcomes. Conclusions: The developmental vitamin D (DVD) model now draws strength from epidemiological evidence of schizophrenia and animal experiments. Although the DVD model does not replicate every aspect of schizophrenia, it has several attractive features: (1) the exposure is based on clues from epidemiology; (2) it reproduces the increase in lateral ventricles; (3) it reproduces well-regarded behavioural phenotypes associated with schizophrenia (e.g. MK- 801 induced hyperlocomotion); and (4) it implicates a disturbance in dopamine signaling. In summary, low prenatal levels of vitamin D can influence critical components of orderly brain development and that this has a long lasting effect on behaviour.

Primary antiphospholipid syndrome in premenopausal women: low vitamin D, high fat mass and maintained bone mineral mass

The aim of this study was to analyze vitamin D levels and their association with bone mineral density and body composition in primary antiphospholipid syndrome. For this cross-sectional study 23 premenopausal women with primary antiphospholipid syndrome (Sapporo criteria) and 23 age- and race-matched healthy controls were enrolled. Demographic, anthropometric, clinical and laboratorial data were collected using clinical interview and chart review. Serum 25-hydroxyvitamin D levels, parathormone, calcium and 24-hour urinary calcium were evaluated in all subjects. Bone mineral density and body composition were studied by dual X-ray absorptiometry. The mean age of patients and controls was 33 years. Weight (75.61 [20.73] vs. 63.14 [7.34] kg, p=0.009), body mass index (29.57 [7.17] vs. 25.35 [3.37] kg, p=0.014) and caloric ingestion (2493 [1005.6] vs. 1990 [384.1] kcal/day, p=0.03) were higher in PAPS than controls. All PAPS were under oral anticoagulant with INR within therapeutic range. Interestingly, biochemical bone parameters revealed lower levels of 25-hydroxyvitamin D [21.64 (11.26) vs. 28.59 (10.67) mg/dl, p=0.039], serum calcium [9.04 (0.46) vs. 9.3 (0.46) mg/dl, p=0.013] and 24-hour urinary calcium [106.55 (83.71) vs. 172.92 (119.05) mg/d, p=0.027] in patients than in controls. Supporting these findings, parathormone levels were higher in primary antiphospholipid syndrome than in controls [64.82 (37.83) vs. 44.53 (19.62) pg/ml, p=0.028]. The analysis of osteoporosis risk factors revealed that the two groups were comparable (p>0.05). Lumbar spine, femoral neck, total femur and whole body bone mineral density were similar in both groups (p>0.05). Higher fat mass [28.51 (12.93) vs. 20.01 (4.68) kg, p=0.005] and higher percentage of fat [36.08 (7.37) vs. 31.23 (4.64)%, p=0.010] were observed in PAPS in comparison with controls; although no difference was seen regarding lean mass. In summary, low vitamin D in primary antiphospholipid syndrome could be secondary to higher weight and fat mass herein observed most likely due to adipocyte sequestration. This weight gain may also justify the maintenance of bone mineral density even with altered biochemical bone parameters. Lupus (2010) 19, 1302-1306.

Vitamin D insufficiency: A risk factor to vertebral fractures in community-dwelling elderly women

Objective:To determine the risk factors for the presence of moderate/severe vertebral fracture, specifically 25-hydroxyvitamin D (25-OHD). Study design: Cross-sectional study conducted for 2 years in the city of Sao Paulo, Brazil including community-dwelling elderly women. Methods: Bone mineral density (BMD), serum 25-OHD, intact parathyroid hormone (iPTH), calcium and estimated glomerular filtration rate (eGFR) were examined in 226 women without vertebral fractures (NO FRACTURE group) and 189 women with at least one moderate/severe vertebral fracture (FRACTURE group). Vertebral fracture assessment (VFA) was evaluated using both the Genant semiquantitative (SQ) approach and morphometry. Results: Patients in the NO FRACTURE group had lower age, increased height, higher calcium intake, and higher BMD compared to those patients in the FRACTURE group (p < 0.05). Of interest, serum levels of 25-OHD in the NO FRACTURE group were higher than those observed in the FRACTURE group (51.73 nmol/L vs. 42.31 nmol/L, p < 0.001). Reinforcing this finding, vitamin D insufficiency (25-OHD < 75 nmol/L) was observed less in the NO FRACTURE group (82.3% vs. 93.65%, p = 0.001). After adjustment for significant variables within the patient population (age, height, race, calcium intake, 25-OHD, eGFR and sites BMD), the logistic-regression analyses revealed that age (OR = 1.09, 95% Cl 1.04-1.14, p < 0.001) femoral neck BMD (OR = 0.7, 95% CI 0.6-0.82, p < 0.001) and 25-OHD <75 nmol/L (OR = 2.38, 95% CI 1.17-4.8, p = 0.016) remains a significant factor for vertebral fracture. Conclusion: Vitamin D insufficiency is a contributing factor for moderate/severe vertebral fractures. This result emphasizes the importance of including this modifiable risk factor in the evaluation of elderly women. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

Human breast tumor slices: A model for identification of vitamin D regulated genes in the tumor microenvironment

While many studies have addressed the direct effects of 1 alpha,25(OH)(2)D(3) on breast cancer (BC) cells, stromal-epithelial interactions, which are important for the tumor development, have been largely ignored. In addition, high concentrations of the hormone, which cannot be attained in vivo, have been used. Our aim was to establish a more physiological breast cancer model, represented by BC tissue slices, which maintain epithelial-mesenchymal interactions, cultured with a relatively low 1 alpha,25(OH)(2)D(3) concentration, in order to evaluate the vitamin D pathway. Freshly excised human BC samples were sliced and cultured in complete culture media containing vehicle, 0.5 nM or 100 nM 1 alpha,25(OH)(2)D(3) for 24 h. BC slices remained viable for at least 24 h, as evaluated by preserved tissue morphology in hematoxylin and eosin (HE) stained sections and bromodeoxyuridine (BrdU) incorporation by 10% of tumor cells. VDR mRNA expression was detected in all samples and CYP24A1 mRNA expression was induced by 1 alpha,25(OH)(2)D(3) in both concentrations (but mainly with 100 nM). Our results indicate that the vitamin D signaling pathway is functional in BC slices, a model which preserves stromal-epithelial interactions and mimics in vivo conditions. (C) 2010 Elsevier Ltd. All rights reserved.

Expression of vitamin D receptor mRNA in the hippocampal formation of rats submitted to a model of temporal lobe epilepsy induced by pilocarpine

Vitamin D (VD), is a steroid hormone with multiple functions in the central nervous system (CNS), producing numerous physiological effects mediated by its receptor (VDR). Clinical and experimental studies have shown a link between VD dysfunction and epilepsy. Along these lines, the purpose of our work was to analyze the relative expression of VDR mRNA in the hippocampal formation of rats during the three periods of pilocarpine-induced epilepsy. Male Wistar rats were divided into five groups: (1) control group; rats that received saline 0.9%, i.p. and were killed 7 days after its administration (CTRL, n = 8), (2) SE group; rats that received pilocarpine and were killed 4 h after SE (SE, n = 8), (3) Silent group-7 days; rats that received pilocarpine and were killed 7 days after SE (SIL 7d, n = 8), (4) Silent group-14 days; rats that received pilocarpine and were killed 14 days after SE (SIL 14d, n = 8), (5) Chronic group; rats that received pilocarpine and were killed 60 days after the first spontaneous seizure, (chronic, n = 8). The relative expression of VDR mRNA was determined by real-time PCR. Our results showed an increase of the relative expression of VDR mRNA in the SIL 7 days, SIL 14 days and Chronic groups, respectively (0.060 +/- 0.024; 0.052 +/- 0.035; 0.085 +/- 0.055) when compared with the CTRL and SE groups (0.019 +/- 0.017; 0.019 +/- 0.025). These data suggest the VDR as a possible candidate participating in the epileptogenesis process of the pilocarpine model of epilepsy. (C) 2008 Elsevier Inc. All rights reserved.

Vitamin D intoxication: a cause of hypocalcaemia and acute renal failure in a HIV patient

Hypercalcaemia in patients with HIV infection is usually associated with specific conditions such as lymphoma and granulomatous diseases. We described a case of severe hypercalcaemia consequent to vitamin D intoxication and secondary renal failure in a HIV patient under tenofovir using. Serum creatinine and calcium returned to near normal levels after vitamin D discontinuation, saline and furosemide administration. Some aspects of the drug-induced nephropathy are discussed.

Vitamin D-Resistant Rickets Type II-A, Basal Ganglia Calcification, and Catatonia: A Casual or Causal Relationship?

Background: Vitamin D-resistant rickets type-IIA (VDRR-IIA) is a rare, congenital, metabolic disorder characterized by hypocalcemia, rickets, and alopecia. There are reports correlating calcium-metabolic disorders with basal ganglia calcification (BGC) and neuropsychiatric symptoms. Objective: The authors document and discuss the relationships of these phenomena. Method: The authors describe a patient born with VDRR-IIA who subsequently developed BGC at age 15, and catatonic symptoms of progressive severity at age 16. Results: There appeared to be a positive correlation between the severity of BGC and neuropsychiatric symptoms. Discussion: This is the first time VDRR-IIA, BGC, and catatonia have been reported in a patient, and the authors discuss the relationship among the conditions. (Psychosomatics 2009; 50: 420-424)

Vitamin D status in a sunny country: Where has the sun gone?

Background & aims: Hypovitaminosis D [serum 25 vitamin D < 30 ng/ml] is related to the development of metabolic bone disease and greater risk of chronic illnesses. However, it is frequently under-diagnosed, mainly in countries where UV radiation is abundant. We prospectively determined the prevalence and the predictors of serum 25 vitamin D (s25(OH)D) in a healthy Brazilian population after the winter and after the summer. Methods: 603 (118M and 485F) healthy Brazilian volunteers aged 18-90 years from a universitary hospital were selected after the winter of 2006. From the initial sample, 209 volunteers (31M and 178F) accepted to participate in a second health check after the subsequent summer. Results: After the winter, median s25(OH)D was 21.4 ng/mL and 77.4% of the population presented hypovitaminosis D. s25(OH)D was significantly related to age, BMI, PTH and race. In multivariate linear regression analysis, s25(OH)D was significantly and independently dependent on age, glycemia and skin color. Significant increase in s25(OH)D was verified after summer [10.6 (3.7-19.3 ng/ml); p < 0.001] and this improvement was dependent on age. We also observed a significant decrease in hyperparathyroidism prevalence (20.8% vs. 4.9%; P < 0.0001). Conclusion: In Sao Paulo, at the end of winter, we observed a high prevalence of hypovitaminosis D and secondary hyperparathyroidism in healthy adults. s25(OH)D was dependent on age and skin color. After summer, we observed a decrease in the prevalence of hypovitaminosis D. This unexpected finding emphasizes the need for a strong recommendation to monitor s25(OH)D, even in a sunny country such as Brazil. (C) 2010 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Vitamin D Receptor and Calcium-Sensing Receptor Gene Polymorphisms in Hypercalciuric Stone-Forming Patients

Background/Aim: Some studies have identified an association of kidney stone formation with vitamin D receptor (VDR) or calcium-sensing receptor (CaSR) polymorphisms. We aimed to evaluate the association between these polymorphisms with urinary calcium excretion (uCa) in calcium-stone-forming patients. Methods: VDR polymorphism, detected by BsmI digestion, and 3 CaSR polymorphisms (G/T at codon 986, G/A at codon 990 and C/G at codon 1011), detected by direct sequencing, were evaluated in 100 hypercalciuric (HCa) and 101 normocalciuric (NCa) calcium-stone-forming patients. Results: The total allelic frequency of VDR polymorphism was: 16% BB, 49% Bb and 35% bb. The prevalence of bb genotype was significantly higher in the HCa when compared to the NCa group (43 vs. 27%). With respect to CaSR polymorphisms, 986S, 990G and 1011E variant alleles were detected, respectively, in 5, 4 and 3% of the whole sample and 5 CaSR haplotypes were identified: 94% ARQ (wildtype), 3% SRQ, 1.5% AGQ, 1.0% ARE and 0.5% AGE. No statistical differences have been observed between NCa and HCa with respect to these CaSR haplotypes. Conclusions: The present study suggested that bb homozygous for VDR polymorphism was overrepresented in hypercalciuric stone formers. Urinary calcium excretion was not associated with CaSR polymorphism in the present sample. Copyright (C) 2009 S. Karger AG, Basel

Benefits of sunlight: Vitamin D deficiency might increase the risk of sudden unexpected death in epilepsy

Epilepsy is the most common serious neurological condition and sudden unexpected death in epilepsy (SUDEP) is the most important direct epilepsy-related cause of death. information concerning risk factors for SUDEP is conflicting, but high seizure frequency is a potential risk factor. Additionally, potential pathomechanisms for SUDEP are unknown, but it is very probable that cardiac arrhythmias during and between seizures or transmission of epileptic activity to the heart via the autonomic nervous system potentially play a role. In parallel, studies have shown a link between vitamin D dysfunction and epilepsy. Moreover, several evidences in the literature suggest an association between low vitamin D and seizures, indicating the possibility of anticonvulsant properties of this hormone. Quite interesting, a growing body of data suggests that low vitamin D levels may adversely affect cardiovascular health, directly associated with death from heart failure and sudden cardiac death. In view of the above findings, our research group focused in this review article that SUDEP, at least in some cases, could be related with low vitamin D levels. (C) 2009 Elsevier Ltd. All rights reserved.

Effects of Lecithin and Vitamin E Supplementation on Liver Steatosis and Oxidative Stress Induced by Chronic Ethanol Consumption in Rats

Oxidative stress and lipid peroxidation, associated with ethanol, are considered important pathogenic mechanisms in the formation of hepatic steatosis. The objective of the present study was to assess the effects of supplementation with lecithin and vitamin E on the oxidatives stress and hepatic steatosis induced in rats by chronic ethanol consumption. Fifty-two Wistar rats were divided into 4 experimental groups: control (AIN-93 diet), ethanol group (control diet plus a 20% hydroalcoholic solution), ethanol + vitamin E group (addition of 0.6% vitamin E to the diet plus a 20% hydroalcoholic solution); ethanol + soy lecithin group (addition of 5 % soy lecithin to the diet plus a 20% hydroalcoholic solution). At the end of 4 weeks the animals were sacrificed. The results showed a significantly smaller number of animals (p < 0.05) classified as having a low degree of steatosis in the ethanol + vitamin E group and ethanol + soy lecithin group compared to the ethanol group. In addition, the ethanol + soy lecithin group had a significantly lower concentration of hepatic fat (p < 0.05) than the ethanol group. A significant reduction of hepatic TBARS concentration (p < 0.05) was detected in the ethanol + vitamin E group compared to the ethanol group. Hepatic carbonyl concentration was significantly lower in the ethanol + soy lecithin group. However, hepatic GSH was significantly lower in the ethanol + vitamin E and ethanol + soy lecithin groups compared to the control group. In conclusion, supplementation with lecithin and vitamin E attenuated the hepatotoxic effects of chronic ethanol intake and contributed to a reduction of the progression of steatosis status.

Impact of maternal vitamin A supplementation on the mother-infant pair in Brazil

Background/Objectives: Vitamin A deficiency (VAD) is a major public health problem. The supplementation of lactating women could be an effective strategy to combat it. The objective of this study was to assess the impact of maternal vitamin A supplementation on the mother-infant pair. Subjects/Methods: This was a double blind, placebo-controlled randomized clinical assay in which 33 women received 200 000 IU of vitamin A and 33 women received soy oil between 20th and 30th postpartum days. Maternal blood and milk samples were collected immediately before supplementation and 3 months after delivery, when blood was also collected from the babies. Retinol concentrations <= 0.70 mu mol/l in serum and 1.05 mu mol/l in milk were considered to indicate VAD. Results: Increase in serum retinol level was observed in the supplemented group compared with the pre-supplementation levels (1.05 and 1.17 mu mol/l, respectively; P = 0.026) and to the post-supplementation levels of the control group (1.02 mu mol/l; P = 0.032). Reduction in breast milk retinol was observed in the control group compared with the pre-supplementation levels (1.93 and 1.34 mu mol/l, respectively; P<0.0001) and to the post-supplementation levels of the supplemented group (1.56 mu mol/l; P = 0.0003). There was significant difference in the prevalence of VAD in breast milk after supplementation, 55.6% (15/27) in the control group and 16.1% (5/31) in the supplemented group (P = 0.002). VAD was present in 66.1% (39/59) of infants, with mean serum retinol levels of 0.64 +/- 0.30 mu mol/l in the control group and of 0.69 +/- 0.26 mu mol/l in the supplemented group. Conclusions: Supplementation had a positive impact on maternal vitamin A status. No effect on infant status was detectable 2 months after supplementation with a single dose. European Journal of Clinical Nutrition (2010) 64, 1302-1307; doi: 10.1038/ejcn.2010.165; published online 15 September 2010