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      Association of admission serum levels of vitamin D, calcium, Phosphate, magnesium and parathormone with clinical outcomes in neurosurgical ICU patients

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          Abstract

          To evaluate the association of admission serum levels of 25(OH)D, parathormone and the related electrolytes with severity of illness and clinical outcomes in neurosurgical critically ill patients, serum levels of 25(OH)D, parathormone, calcium, magnesium, and phosphate, along with APACHE II score were measured for 210 patients upon admission. Mean serum 25(OH)D was 21.1 ± 7.4 ng/mL. 25(OH)D deficiency (less than 20 ng/dL) and elevated serum parathormone level were found in 47.6% and 38% of patients respectively. Hypocalcaemia, hypophosphatemia, hypomagnesaemia and hypermagnesaemia were found in 29.5%, %63.8, 41.9% and 27.6% of patients respectively. The APACHE II score was significantly correlated with serum levels of 25(OH)D, parathormone, calcium, and phosphate. Multivariate regression analysis adjusted by other risk factors showed that among all clinical outcomes, admission hypovitaminosis D was associated with longer duration of ICU stay and a high admission of parathormone was associated with in ICU mortality. We concluded that disorders of admission serum levels of 25(OH)D, parathormone, calcium, magnesium, and phosphate are related to the presence of multiple causal factors such as severity of disease and are not independently associated with clinical outcomes. Most often they are normalize spontaneously with resolution of the disease process.

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          In vivo evidence for a novel pathway of vitamin D₃ metabolism initiated by P450scc and modified by CYP27B1.

          We define previously unrecognized in vivo pathways of vitamin D(3) (D3) metabolism generating novel D3-hydroxyderivatives different from 25-hydroxyvitamin D(3) [25(OH)D3] and 1,25(OH)(2)D3. Their novel products include 20-hydroxyvitamin D(3) [20(OH)D3], 22(OH)D3, 20,23(OH)(2)D3, 20,22(OH)(2)D3, 1,20(OH)(2)D3, 1,20,23(OH)(3)D3, and 17,20,23(OH)(3)D3 and were produced by placenta, adrenal glands, and epidermal keratinocytes. We detected the predominant metabolite [20(OH)D3] in human serum with a relative concentration ∼20 times lower than 25(OH)D3. Use of inhibitors and studies performed with isolated mitochondria and purified enzymes demonstrated involvement of the steroidogenic enzyme cytochrome P450scc (CYP11A1) as well as CYP27B1 (1α-hydroxylase). In placenta and adrenal glands with high CYP11A1 expression, the predominant pathway was D3 → 20(OH)D3 → 20,23(OH)(2)D3 → 17,20,23(OH)(3)D3 with further 1α-hydroxylation, and minor pathways were D3 → 25(OH)D3 → 1,25(OH)(2)D3 and D3 → 22(OH)D3 → 20,22(OH)(2)D3. In epidermal keratinocytes, we observed higher proportions of 22(OH)D3 and 20,22(OH)(2)D3. We also detected endogenous production of 20(OH)D3, 22(OH) D3, 20,23(OH)(2)D3, 20,22(OH)(2)D3, and 17,20,23(OH)(3)D3 by immortalized human keratinocytes. Thus, we provide in vivo evidence for novel pathways of D3 metabolism initiated by CYP11A1, with the product profile showing organ/cell type specificity and being modified by CYP27B1 activity. These findings define the pathway intermediates as natural products/endogenous bioregulators and break the current dogma that vitamin D is solely activated through the sequence D3 → 25(OH)D3 → 1,25(OH)(2)D3.
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            Detection of novel CYP11A1-derived secosteroids in the human epidermis and serum and pig adrenal gland

            To investigate whether novel pathways of vitamin D3 (D3) and 7-dehydrocholesterol (7DHC) metabolism initiated by CYP11A1 and previously characterized in vitro, occur in vivo, we analyzed samples of human serum and epidermis, and pig adrenals for the presence of intermediates and products of these pathways. We extracted human epidermis from 13 individuals and sera from 13 individuals and analyzed them by LC/qTOF-MS alongside the corresponding standards. Pig adrenal glands were also analyzed for these steroids and secosteroids. Epidermal, serum and adrenal samples showed the presence of D3 hydroxy-derivatives corresponding to 20(OH)D3, 22(OH)D3, 25(OH)D3, 1,25(OH)2D3, 20,22(OH)2D3, 20,23(OH)2D3, 20,24(OH)2D3, 20,25(OH)2D3, 20,26(OH)2D3, 1,20,23(OH)3D3 and 17,20,23(OH)3D3, plus 1,20(OH)2D3 which was detectable only in the epidermis. Serum concentrations of 20(OH)D3 and 22(OH)D3 were only 30- and 15-fold lower than 25(OH)D3, respectively, and at levels above those required for biological activity as measured in vitro. We also detected 1,20,24(OH)3D3, 1,20,25(OH)3D3 and 1,20,26(OH)3D3 in the adrenals. Products of CYP11A1 action on 7DHC, namely 22(OH)7DHC, 20,22(OH)27DHC and 7-dehydropregnenolone were also detected in serum, epidermis and the adrenal. Thus, we have detected novel CYP11A1-derived secosteroids in the skin, serum and adrenal gland and based on their concentrations and biological activity suggest that they act as hormones in vivo.
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              Effects of age and serum 25-OH-vitamin D on serum parathyroid hormone levels.

              Several studies define optimal serum 25-hydroxyvitamin D (25-OHD) levels based on serum PTH level reaching an asymptote. However, results differ widely, ranging from 25-OHD levels of 12-44 ng/ml: many studies are constrained by small sample size. The objective of the study was to determine the relationship between serum PTH and 25-OHD levels and age in a very large reference laboratory database. This was a detailed cross-sectional analysis of 312,962 paired serum PTH and 25-OHD levels measured from July 2010 to June 2011. Median PTH levels and the proportion of patients (PTH > 65 pg/ml), from 63 successive 25-OHD frequency classes of 5000 patients, provide smooth, exceptionally well-fitted curves (R(2) = 0.994 and R(2) = 0.995, respectively) without discernible inflection points or asymptotes but with striking age dependencies. Serum 25-OHD was below the recent Institute of Medicine sufficiency guidance of 20 ng/ml in 27% (85,000) of the subjects. More importantly, 40 and 51% of subjects (serum 25-OHD 65 pg/ml). This analysis, despite inevitable inherent limitations, introduces several clinical implications. First, median 25-OHD-dependent PTH levels revealed no threshold above which increasing 25-OHD fails to further suppress PTH. Second, the large number of subjects with 25-OHD deficiency and hyperparathyroidism reinforces the Third International Workshop on Asymptomatic Primary Hyper parathyroidism's recommendations to test for, and replete, vitamin D depletion before considering parathyroidectomy. Third, strong age dependency of the PTH-25-OHD relationship likely reflects the composite effects of age-related decline in calcium absorption and renal function. Finally, this unselected large population database study could guide clinical management of patients based on an age-dependent, PTH-25-OHD continuum.
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                Author and article information

                Contributors
                nutritiondata@yahoo.com
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                14 February 2018
                14 February 2018
                2018
                : 8
                : 2965
                Affiliations
                [1 ]GRID grid.411600.2, Department of Anesthesiology and Critical Care, Shohada Tajrish Hospital, , Shahid Beheshti University of Medical Sciences, ; Tehran, Iran
                [2 ]GRID grid.411600.2, National Nutrition and Food Technology Research Institute, Faculty of Nutrition and Food Technology, , Shahid Beheshti University of Medical Sciences, ; Tehran, Iran
                [3 ]GRID grid.411600.2, Department of Biostatistics, School of Public Health, , Shahid Beheshti University of Medical Sciences, ; Tehran, Iran
                Article
                21177
                10.1038/s41598-018-21177-4
                5813225
                29445220
                66610fac-8c44-43a2-bb91-999d7d390315
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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                : 27 October 2017
                : 29 January 2018
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