Vitamin D represses rhinovirus replication in cystic fibrosis cells by inducing LL-37.

Vitamin D has immunomodulatory properties in the defence against pathogens. Its insufficiency is a widespread feature of cystic fibrosis (CF) patients, which are repeatedly suffering from rhinovirus (RV)-induced pulmonary exacerbations.To investigate whether vitamin D has antiviral activity, primary bronchial epithelial cells from CF children were pre-treated with vitamin D and infected with RV16. Antiviral and anti-inflammatory activity of vitamin D was assessed. RV and LL-37 levels were measured in bronchoalveolar lavage (BAL) of CF children infected with RV.Vitamin D reduced RV16 load in a dose-dependent manner in CF cells (10(-7 )M, p<0.01). The antiviral response mediated by interferons remained unchanged by vitamin D in CF cells. Vitamin D did not exert anti-inflammatory properties in RV-infected CF cells. Vitamin D increased the expression of the antimicrobial peptide LL-37 up to 17.4-fold (p<0.05). Addition of exogenous LL-37 decreased viral replication by 4.4-fold in CF cells (p<0.05). An inverse correlation between viral load and LL-37 levels in CF BAL (r=-0.48, p<0.05) was observed.RV replication in primary CF bronchial cells was reduced by vitamin D through the induction of LL-37. Clinical studies are needed to determine the importance of an adequate control of vitamin D for prevention of virus-induced pulmonary CF exacerbations.

New insights into the role of the duodenal vitamin D receptor in calcium homeostasis

It is generally believed that 1,25(OH)2D3, bound to its receptor (VDR) contributes to calcium homeostasis by regulating active calcium absorption in the proximal small intestine. However, studying patients with hereditary vitamin D-resistant rickets (HVDRR) provided investigators with a better understanding of VDR's role in calcium homeostasis. HVDRR patients have inactivating mutations in the VDR, and as a consequence they develop hypocalcemia, hyperparathyroidism and severe rickets. However, these phenotypes can be corrected if the patients are given IV infusions of calcium or dietary calcium. This raises the question of what is the physiological significance of VDR-regulated active calcium absorption if calcium homeostasis can be restored independently of the VDR. ^ In order to distinguish the contribution of VDR in the proximal small intestine to overall calcium homeostasis, I generated transgenic mice expressing the human VDR (hVDR) exclusively in the proximal small intestine of mVDR-/- mice by using an hVDR-expressing transgene driven by the duodenal-specific adenosine deaminase enhancer (hVDR+/mVDR-/-). hVDR+/mVDR-/- mice expressed transcriptionally active hVDR only in the proximal small intestine and responded to 1,25(OH)2D3 by up-regulating expression of TRPV6 and calbindin D9K, genes involved in calcium absorption. Furthermore, ligated duodenal loop assays determined that calcium absorption in hVDR+/mVDR-/- mice was as responsive to 1,25(OH)2D3 as in WT mice. Despite having a functional hVDR in the proximal small intestine, hVDR+/mVDR-/- mice were hypocalcemic, had hyperparathyroidism, and were rachitic when fed a normal rodent diet at weaning, as were the mVDR-/- mice. However, when fed a high calcium, phosphorus, and lactose diet (rescue diet), the hVDR+/mVDR-/- mice responded more effectively than the mVDR-/- mice by down-regulation of parathyroid hormone production and by a greater increase in bone mineralization. Furthermore, when three-month-old rachitic mice were fed a rescue diet for 3 weeks, serum calcium and bone mineral content were normalized in hVDR+/mVDR-/- mice, but not in mVDR-/- mice. ^ In conclusion, hVDR expression enabled young mice to better use the rescue diet than mVDR-/- mice. Expression of transgenic hVDR also protected the ability of older mice to respond to the rescue diet despite the absence of the VDR elsewhere in the intestinal tract. I propose that because hVDR+/mVDR-/- mice responded better than mVDR-/- mice to the rescue diet, it is likely that VDR expression in the proximal small intestine is necessary in nutritional (insufficient dietary calcium) and physiological (age) conditions when passive calcium absorption is inadequate. ^

Re-emerging Vitamin D deficiency epidemic and its implications on the public health in the US

Vitamin D is essential in maintaining the bone health and Calcium homeostasis in the body. These actions are mediated through the Vitamin D receptors (VDR) present in cells through which the activated vitamin D acts [1]. In the past, it was known that these receptors existed in the intestine and bone cell. However, recent discovery of VDR in other tissues as well, has broadened the action of Vitamin D and increased its adequate intake [1].^ In the past, Vitamin D deficiency was most common among institutionalized, elderly patients and children and thought to be extinct in the healthy population. However, recent evidence has shown that, prevalence of vitamin D deficiency is increasing into an epidemic status in the overall population of the United States, including the healthy individuals [2-3]. The increased daily-recommended requirement and other multiple factors are responsible for the re-emergence of this epidemic [4-5]. Some of these factors could be used to control the epidemic. Studies have also shown the association between vitamin D deficiency and increased risk for developing chronic diseases such as diabetes, hypertension, multiple sclerosis, arthritis, and some fatal cancers like prostate, colon and breast cancers [1, 4, 6-14]. This issue results in increased disease burden, morbidity and mortality in the community [15-20].^ Methods: The literature search was conducted using the University of Texas Health Science Center at Houston (UTHSC) and University of Texas Southwestern Medical Center (UTSW) online library. The key search terms used are “vitamin D deficiency And prevalence Or epidemiology”, “vitamin D deficiency And implication And public health” using PubMed and Mesh database and “vitamin D deficiency” using systematic reviews. The search is limited to Humans and the English language. The articles considered for the review are limited to Healthy US population to avoid health conditions that predispose the population to vitamin D deficiency. Only US population is considered to narrow down the study.^ Results: There is an increased prevalence of low levels of Vitamin D levels below the normal range in the US population regardless of age and health status. Vitamin D deficiency is also associated with increased risk of chronic illnesses and fatal cancers.^ Conclusion: This increased prevalence and the association of the deficiency with increased all-cause mortality has increased the economic burden and compromised the quality of life among the population. This necessitates the health care providers to routinely screen their patients for the Vitamin D status and counsel them to avoid the harmful effects of the Vitamin D deficiency. ^

AN INVESTIGATION OF THE MODIFYING EFFECTS OF VITAMIN A AND HYPOXIC CELL SENSITIZERS IN RADIATION CARCINOGENESIS IN MICE

The effect of vitamin A (retinyl acetate) and three hypoxic cell sensitizers (metronidazole, misonidazole and desmethylmisonidazole) on lung tumor development in strain A mice exposed to radiation was assessed.^ In experiments involving vitamin A, two groups of mice were fed a low vitamin A diet (< 100 IU/100g diet) while the two other groups were fed a high vitamin A diet (800 IU/100g diet). After two weeks one group maintained on the high vitamin A diet and one group maintained on the low vitamin A diet were given an acute dose of 500 rad of gamma radiation to the thoracic region. The circulating level of plasma vitamin A in all four groups of mice was monitored. A difference in circulating vitamin A in the mice maintained on high and low vitamin A diet became evident by 20 weeks and continued for the duration of the experiment. Mice were killed 18, 26, and 40 weeks post irradiation, their lungs were removed and the number of surface adenomas were counted. There was a significant increase in the number of mice bearing lung tumors and the mean number of lung tumors per mouse in the irradiated group maintained on the high vitamin A diet at 40 weeks post irradiation as compared to the irradiated group maintained on a low vitamin A diet (p < 0.05). Under the conditions of this experiment the development of pulmonary adenomas in irradiated strain A mice appears to relate directly to circulating levels of vitamin A.^ In the other experiment two dose levels of the hypoxic cell sensitizers, 0.2mg/g and 0.6mg/g, were used either alone or in combination with 900 rad of gamma radiation in a fractionated dose schedule of twice a week for three weeks. In the groups of mice which received hypoxic cell sensitizers only, the prevalence and the mean number of lung tumors per mouse were somewhat increased (p < 0.10) in the higher dose group (0.6mg/g) of misonidazole but was not significantly different from the control animals in the other two sensitizer groups. The combination of hypoxic cell sensitizer and radiation did not show any significant enhancement of lung tumor response when compared with the group which received radiation only. The dose of radiation used in this study significantly enhanced lung tumor formation in mice when compared with the control group. Thus, under the experimental exposure conditions used in this investigation, which were very similar to the exposure conditions occurring in clinical treatment, all three hypoxic cell sensitizers did not sensitize the mouse to the carcinogenic effects of gamma radiation.^

Assessment of executive function before and after vitamin D replacement in vulnerable adults who self-neglect

Purpose: Self-neglect (SN) is the inability to maintain self-care needs. It is thought that older adults who have impaired executive function (EF) develop the inability to do self-care and to protect themselves. The specific aims were to (1) determine the feasibility of using multiple EF measures with community-dwelling elders with SN, (2) identify changes in EF between baseline and 5-months in community-dwelling elders with SN who receive 50,000 IU or 400 IU of oral vitamin D monthly and (2) explore changes in specific dimensions of EF between the groups. ^ Methods: Fifty adults, 65 years of age and older, were recruited from Adult Protective Services with confirmed SN. A research nurse administered the following tests at baseline and five-months: Delis-Kaplan Card Sort Test (D-KEFS), Executive Interview (EXIT 25), CLOX Drawing Test (CLOX I, II), Trails Making Test A and B (TMT A & B) and the Mini-Mental State Examination (MMSE). Demographic data was collected at baseline and serum 25-OHD levels were collected at baseline and five-months. ^ Results: Older adults with SN were more likely to fail the CLOX1 and D-KEFS, while passing the MMSE, CLOX II, TMT A & B and the EXIT 25. At five-months, the only statistically significant difference between groups was in the TMT A & B test scores; the control group did better than the treatment group. There was a non-significant increase in serum vitamin D levels for both groups and no difference between groups. ^ Conclusions: Results from this study provide support that individuals who SN will complete a battery of EF tests and that they exhibit the following impairments consistent with executive dysfunction: 'concept generation', 'planning', 'inhibition', and 'spatial working memory'. Utilizing only one EF measure in individuals with intact cognition may result in unidentification of individuals with executive dysfunction, thus delaying necessary treatment. Future studies should attempt to determine different etiologies of executive dysfunction and determine if early treatment can prevent or reverse SN. ^ Key Words: Self-neglect, Executive Dysfunction, Executive Function, Adult Protective Services, Community-dwelling, Vitamin D ^

Vitamin A supplementation in very low birth weight infants

PURPOSE: In United States, the percentage of Extremely Low Birth Weight (ELBW) born for year 2006 was 0.8% (approximately 32,000 babies) & Very Low Birth Weight (VLBW) 1.48% (1). ELBW babies account for nearly half (49%) of the infant mortality for United States. Very Low birth weight infants are at a significant risk for high mortality and morbidity due to their multi system involvement and predisposition to lung prematurity and impaired immune function. One of the common causes cited is Vitamin A deficiency (2, 3).The purpose of this study is to look at published literature on Vitamin A supplementation in very low birth weight (VLBW) infants. ^ RESEARCH DESIGN: Systematic review of literature of published articles meeting the pre-defined criteria. ^ PROCEDURE: Studies included in this review were those which looked at very low birth weight infants defined as birth weight<1500gms. All experimental studies were reviewed. Studies looking at the effect of Vitamin A supplementation in comparison with a placebo or by itself in varying dosing regimens as an intervention were reviewed. Vitamin A deficiency and its manifestations were of interest. We used key words such as "very low birth weight", "mortality", "Vitamin A", "retinol" and "supplementation" in our search. ^ RISKS & POTENTIAL BENEFITS: We do not see any potential risks associated with this study. The potential benefit is recommendation for future studies based on the review of literature available currently. ^ IMPORTANCE OF KNOWLEDGE THAT MAY REASONABLY BE EXPECTED TO RESULT: The systematic review of literature of all experimental studies in VLBW infants showed uniform correlation of parenteral Vitamin A dosing and high plasma concentrations achieved. The recommended dosage for use is 5000 IU 3 times/week given intramuscularly for 4 weeks to prevent CLD. Higher doses have not shown benefit, with a potential for toxicity, while lower doses are inadequate. There is no role of use of Vitamin A in closure of patent ductus arteriosus & reducing mortality. However, it is important to state that the number of studies done so far is limited with small sample sizes. There is a need in the future for experimental studies to ascertain the role of Vitamin A to improve outcomes in VLBW. Atleast, one more RCT should be conducted using the dosage recommended above to make this a standard practice.^

(Table 1) Retinol (vitamin A) and alpha-tocopherol (vitamin E) concentration in polar bear (Ursus maritimus) kidney

Vitamins A and E content of inner organs, among these the kidneys, are increasingly being used as an indicator of adverse effects caused to the organism by e.g. environmental contaminants. In general, only a renal sub sample is used for analyses, and it is thus essential to know which part of the organ to sample in order to get a representative value for this important biomarker. The aim here was to assess the distribution of vitamins A (retinol) and E (alpha-tocopherol) within the polar bear multireniculate kidney (i.e. polar vs. medial position) and also within the cortex vs. medulla of each separate renculi. The results showed no significant difference between the medial and polar renculi with regards to either retinol (p = 0.44) or alpha-tocopherol (p = 0.75). There were, however, significant differences between cortex and medulla for both vitamins (retinol, p = 0.0003; alpha-tocopherol, p<0.0001). The kidney cortex contained higher values of both vitamins than the medulla; on average 29% more retinol and 57% more alpha-tocopherol. Mean concentrations in the medulla was 2.7 mg/kg for retinol and 116 mg/kg for alpha-tocopherol, and in the cortex 3.5 mg/kg for retinol and 182 mg/kg for alpha-tocopherol. These results clearly indicate that one should take precautions when analyzing retinol and alpha-tocopherol in polar bear kidneys. Prior to analysis, the renculi should be separated into medulla and cortex. The results indicated no significant differences between renculi from different parts of the kidney.