BackgroundSuboptimal vitamin D status is common in people with celiac disease (CeD), a disease that can be characterized by the presence of serum anti-tissue transglutaminase antibodies (TG2A) (i.e... Show moreBackgroundSuboptimal vitamin D status is common in people with celiac disease (CeD), a disease that can be characterized by the presence of serum anti-tissue transglutaminase antibodies (TG2A) (i.e., TG2A positivity). To date, it remains unclear whether childhood TG2A positivity is associated with vitamin D status and how this potential association can be explained by other factors than malabsorption only, since vitamin D is mainly derived from exposure to sunlight. The aim of our study was therefore to assess whether childhood TG2A positivity is associated with vitamin D concentrations, and if so, to what extent this association can be explained by sociodemographic and lifestyle factors.MethodsThis cross-sectional study was embedded in the Generation R Study, a population-based prospective cohort. We measured serum anti-tissue transglutaminase antibodies (TG2A) concentrations and serum 25-hydroxyvitamin D (25(OH)D) concentrations of 3994 children (median age of 5.9 years). Children with serum TG2A concentrations >= 7 U/mL were considered TG2A positive. To examine associations between TG2A positivity and 25(OH)D concentrations, we performed multivariable linear regression, adjusted for sociodemographic and lifestyle factors.ResultsVitamin D deficiency (serum 25(OH)D < 50 nmol/L) was found in 17 out of 54 TG2A positive children (31.5%), as compared to 1182 out of 3940 TG2A negative children (30.0%). Furthermore, TG2A positivity was not associated with 25(OH)D concentrations (beta -2.20; 95% CI -9.72;5.33 for TG2A positive vs. TG2A negative children), and this did not change after adjustment for confounders (beta -1.73, 95% CI -8.31;4.85).ConclusionsOur findings suggest there is no association between TG2A positivity and suboptimal vitamin D status in the general pediatric population. However, the overall prevalence of vitamin D deficiency in both populations was high, suggesting that screening for vitamin D deficiency among children, regardless of TG2A positivity, would be beneficial to ensure early dietary intervention if needed. Show less
This thesis starts with a comprehensive review of the literature on the role of vitamin D in fracture healing. Followed by three clinical studies on the prevalence of vitamin D deficiency in... Show moreThis thesis starts with a comprehensive review of the literature on the role of vitamin D in fracture healing. Followed by three clinical studies on the prevalence of vitamin D deficiency in fracture patients, risk factors and effect of vitamin D status on fracture healing. The second part of this thesis begins with an extensive review on the effect of osteoporosis and its treatment on fracture healing. A retrospective study is performed on the effect of osteoporosis on fracture healing. Also a more fundamental study on osteoporosis is performed, levels of sclerostin are determined in fracture patients with osteoporosis as biomarker. In the appendix of this thesis, two case reports are presented which illustrate the role of vitamin D plays in bone metabolism and fracture healing.Overall, vitamin D plays a role in fracture healing, although the exact mechanismremains not fully elucidated. The influence of vitamin D deficiency on fracturehealing cannot be fully ignored, but the exact degree of influence is not determined yet.Since the high prevalence of vitamin D deficiency found among adult and paediatricfracture patients, clinicians should be aware of vitamin D deficiency and the prevailingadvice regarding vitamin D supplementation, especially in case of delayed fractureunion or fracture non union.Although animal studies show a negative effect of osteoporosis on fracture healing,convincing clinical evidence lack to support this potential association. Since no negativeeffect of anti-osteoporosis medication on fracture healing could be determined inpatients, treatment should not be withheld in case of a fracture. Show less
Stokes, C.S.; Weber, D.; Wagenpfeil, S.; Stuetz, W.; Moreno-Villanueva, M.; Dolle, M.E.T.; ... ; Grune, T. 2021
Self-rated health (SRH) is associated with higher risk of death. Since low plasma levels of fat-soluble vitamins are related to mortality, we aimed to assess whether plasma concentrations of... Show moreSelf-rated health (SRH) is associated with higher risk of death. Since low plasma levels of fat-soluble vitamins are related to mortality, we aimed to assess whether plasma concentrations of vitamins A, D and E were associated with SRH in the MARK-AGE study. We included 3158 participants (52 % female) aged between 35 and 75 years. Cross-sectional data were collected via questionnaires. An enzyme immunoassay quantified 25-hydroxyvitamin D and HPLC determined alpha-tocopherol and retinol plasma concentrations. The median 25-hydroxyvitamin D and retinol concentrations differed significantly (P < 0.001) between SRH categories and were lower in the combined fair/poor category v. the excellent, very good and good categories (25-hydroxvitamin D: 40.8 v. 51.9, 49.3, 46.7 nmol/l, respectively; retinol: 1.67 v. 1.75, 1.74, 1.70 mu mol/l, respectively). Both vitamin D and retinol status were independently associated with fair/poor SRH in multiple regression analyses: adjusted OR (95 % CI) for the vitamin D insufficiency, deficiency and severe deficiency categories were 1.33 (1.06-1.68), 1.50 (1.17-1.93) and 1.83 (1.34-2.50), respectively; P = 0.015, P = 0.001 and P < 0.001, and for the second/third/fourth retinol quartiles: 1.44 (1.18-1.75), 1.57 (1. 28-1.93) and 1.49 (1.20-1.84); all P < 0.001. No significant associations were reported for a-tocopherol quartiles. Lower vitamin A and D status emerged as independent markers for fair/poor SRH. Further insights into the long-term implications of these modifiable nutrients on health status are warranted. Show less
The prevalence of hypovitaminosis D is currently increasing. A wide variety of diseases and complications are associated with low vitamin D serum concentrations, including poor fracture healing and... Show moreThe prevalence of hypovitaminosis D is currently increasing. A wide variety of diseases and complications are associated with low vitamin D serum concentrations, including poor fracture healing and fracture non-union. A healthy 44-y-old man presented himself with pain due to a non-union of a femoral shaft fracture at 4 y after the initial injury. The fracture had been operated upon three times and was adequately fixated in anatomic position. Hypovitaminosis D was diagnosed, and subsequent supplementation resulted in complete union of the fracture with full pain relief. This case illustrates the importance of adequate serum vitamin D levels in fracture healing, in addition to other fracture healing facilitating factors. With the increasing prevalence of hypovitaminosis D and possibly associated fracture-related complications, routine vitamin D determination should become part of clinical workup in cases of fracture non-union. (c) 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) Show less
Vitamin D plays an active role in the modulation of innate and adaptive immune responses as well as in the protection against respiratory pathogens, e.g. by increasing expression of the... Show moreVitamin D plays an active role in the modulation of innate and adaptive immune responses as well as in the protection against respiratory pathogens, e.g. by increasing expression of the antimicrobial peptide hCAP18/LL-37. The main aim of this thesis was to elucidate the role of inflammation on the protective effects of vitamin D on respiratory host defense responses in chronic inflammatory lung diseases such as chronic obstructive pulmonary disease (COPD). Airway epithelial host defense responses in COPD patients are defective and these patients are therefore more susceptible to respiratory infections. In this thesis we have shown that exposure to cigarette smoke, a main risk factor for COPD, reduced expression of certain host defense mediators by affecting end-stage airway epithelial differentiation and might explains why COPD patients are more susceptible to respiratory infections. We have further demonstrated in the studies presented in this thesis that certain airway inflammatory mediators could possibly interfere with vitamin D metabolism by promoting expression of vitamin D degrading enzyme CYP24A1, thereby reducing local levels of vitamin D and accompanying protective antimicrobial and anti-inflammatory actions. These new insights may yield possible new strategies to target CYP24A1 that enhance local levels and signaling of vitamin D to increase protection against exacerbations in COPD patients. Show less
Rafiq, R.; Haddaoui, H. el; Mutsert, R. de; Rosendaal, F.R.; Hiemstra, P.S.; Cobbaert, C.M.; ... ; Jongh, R.T. de 2020
Objective: The role of adiposity in the relationship between vitamin D and inflammation is unknown. Our aim was therefore to assess the association of serum 25-hydroxyvitamin D (25(OH)D) with C... Show moreObjective: The role of adiposity in the relationship between vitamin D and inflammation is unknown. Our aim was therefore to assess the association of serum 25-hydroxyvitamin D (25(OH)D) with C-reactive protein (CRP), leptin and adiponectin and the role of adiposity in this relationship.Methods: This is a cross-sectional analysis of The Netherlands Epidemiology of Obesity Study (NEO), a population-based cohort study in men and women aged 45 to 65 years. Main outcome measures were CRP, leptin and adiponectin. In the linear regression analyses we adjusted for age, sex, ethnicity, creatinine, education, alcohol use, smoking status, physical activity, number of chronic diseases, season, total body fat and waist circumference.Results: Of the 6287 participants, 21% were vitamin D deficient (serum 25(OH)D < 50 nmol/L). Mean (SD) age and BMI were 56 (6) years and 26.3 (4.4) kg/m(2), respectively. Although after adjustment for most examined potential confounders, each 10 nmol/L increase in serum 25(OH)D was associated with 2.3% (95%CI: -4.0 to -0.5) lower CRP, 3.5% (-4.7 to -2.2) lower leptin, and 0.13 ng/mL (0.04-0.21) higher adiponectin, most of these associations seemed to largely stem from an additional potential confounder - adiposity - as they either disappeared (leptin and CRP) or were largely diminished (adiponectin) upon further adjustment for adiposity indices (total body fat and waist circumference).Conclusion: We found that measures of adiposity largely explained the negative association of serum 25(OH)D with the pro-inflammatory CRP and leptin, and the positive association with the anti-inflammatory adiponectin. These results suggest that future studies should take the effect of adiposity into account. Show less
Airway epithelium is an important site for local vitamin D (VD) metabolism; this can be negatively affected by inflammatory mediators. VD is an important regulator of respiratory host defense, for... Show moreAirway epithelium is an important site for local vitamin D (VD) metabolism; this can be negatively affected by inflammatory mediators. VD is an important regulator of respiratory host defense, for example, by increasing the expression of hCAP18/LL-37. TGF-beta 1 is increased in chronic obstructive pulmonary disease (COPD), and known to decrease the expression of constitutive host defense mediators such as secretory leukocyte protease inhibitor (SLPI) and polymeric immunoglobulin receptor (pIgR). VD has been shown to affect TGF-beta 1-signaling by inhibiting TGF-beta 1-induced epithelial-to-mesenchymal transition. However, interactions between VD and TGF-beta 1, relevant for the understanding host defense in COPD, are incompletely understood. Therefore, the aim of the present study was to investigate the combined effects of VD and TGF-beta 1 on airway epithelial cell host defense mechanisms. Exposure to TGF-beta 1 reduced both baseline and VD-induced expression of hCAP18/LL-37, partly by increasing the expression of the VD-degrading enzyme CYP24A1. TGF-beta 1 alone decreased the number of secretory club and goblet cells and reduced the expression of constitutive host defense mediators SLPI, s/lPLUNC and pIgR, effects that were not modulated by VD. These results suggest that TGF-beta 1 may decrease the respiratory host defense both directly by reducing the expression of host defense mediators, and indirectly by affecting VD-mediated effects such as expression of hCAP18/LL-37. Show less
Rafiq, R.; Walschot, F.; Lips, P.; Lamb, H.J.; Roos, A. de; Rosendaal, F.R.; ... ; Mutsert, R. de 2019
Background & aims: Obesity is a well-established risk factor of vitamin D deficiency. However, it is unclear which fat deposit is most strongly related to serum 25-hydroxyvitamin D (25(OH)D)... Show moreBackground & aims: Obesity is a well-established risk factor of vitamin D deficiency. However, it is unclear which fat deposit is most strongly related to serum 25-hydroxyvitamin D (25(OH)D) concentrations. Our aim was to distinguish the specific contributions of total body fat (TBF), abdominal subcutaneous adipose tissue (aSAT), visceral adipose tissue (VAT) and hepatic fat on 25(OH)D concentrations.Methods: We performed a cross-sectional analysis of the Netherlands Epidemiology of Obesity study, a population-based cohort study. We used linear regression analyses to examine associations of TBF, aSAT, VAT (n = 2441) and hepatic fat (n = 1980) with 25(OH)D concentrations. Standardized values were used to compare the different fat deposits.Results: Mean (SD) age and 25(OH)D concentrations of the study population was 56 (6) years and 70.8 (24.2) nmol/L, respectively. TBF was inversely associated with 25(OH)D concentrations in women, but not in men. One percent higher TBF was associated with 0.40 nmol/L (95%CI: -0.67 to -0.13) lower 25(OH)D. aSAT was not associated with 25(OH)D concentrations. One cm 2 higher VAT was associated with 0.05 nmol/L (-0.09 to -0.02) lower 25(OH)D in men, and 0.06 nmol/L (-0.10 to -0.01) lower 25(OH)D in women. Hepatic fat was only associated with 25(OH)D in men. A tenfold increase in hepatic fat was associated with 6.21 nmol/L (-10.70 to -1.73) lower 25(OH)D. Regressions with standardized values showed VAT was most strongly related to 25(OH)D.Conclusions: In women, TBF and VAT were inversely related to 25(OH)D concentrations. In men, VAT and hepatic fat were inversely related to 25(OH)D concentrations. In both groups, VAT was most strongly associated with 25(OH)D concentrations. (C) 2018 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved. Show less
Blood for determining 25-hydroxyvitamin D-3 [25(OH)D-3] is usually obtained through venipuncture although, as an alternative for serum, dried blood spot (DBS) can be considered. The aim of this... Show moreBlood for determining 25-hydroxyvitamin D-3 [25(OH)D-3] is usually obtained through venipuncture although, as an alternative for serum, dried blood spot (DBS) can be considered. The aim of this proof-of-concept study was to investigate levels of agreement between measurements of 25(OH)D-3 obtained with DBS compared with serum. 301 Chinese participants were included who completed 25(OH)D-3 measurement from DBS and from simultaneously collected blood samples obtained by venipuncture. Measurements of both DBS and serum 25(OH)D-3 were performed using liquid chromatography followed by tandem mass spectrometry. Agreement between the two methods was assessed with Passing and Bablok regression analysis and Bland-Altman plot.Measurements showed a good correlation (Pearson's correlation coefficient r = 0.929, P < 0.001) between the two methods. After recalculating for a 13% difference, a regression equation of DBS 25(OH)D-3 = -1.91 + 1.00 serum 25(OH)D-3 was found in Passing and Bablok regression analysis. Bland-Altman analysis showed a fixed bias of 1.7 nmol/L; upper and lower limit of agreement was 24.1 nmol/L and -20.7 nmol/L, respectively.Sensitivity of recalculated DBS for 25(OH)D-3 concentrations < 30 and < 50 nmol/L was 87.8% and 91.1%, respectively, and specificity was 89.2% and 83.1%, respectively.In conclusion, a good agreement was found between the measurement of 25(OH)D-3 obtained with DBS compared with serum. DBS may possibly be used in a future screening program, but it is less suitable for individualized vitamin D status assessment. Show less
Weighing the strengths and limitations of our studies, we believe our results contribute to the unraveling of causal pathways between obesity and lung function impairment. The main conclusion of... Show moreWeighing the strengths and limitations of our studies, we believe our results contribute to the unraveling of causal pathways between obesity and lung function impairment. The main conclusion of the first part of this thesis is that visceral fat is associated with lung function impairment in men with the metabolic syndrome. Furthermore, we conclude that in the general population there is no causal association between insulin resistance and lung function, nor an association between visceral fat and exhaled nitric oxide. In the second part of this thesis we showed that vitamin D is associated with lung function and nitric oxide in obese participants.In the study presented in this thesis antimicrobial peptides levels were lower in allergic asthmatics than in healthy controls. Unfortunately, we were not able to conclude if vitamin D supplementation influences these antimicrobial peptide levels. Larger studies are needed to investigate whether vitamin D also increases antimicrobial peptides in the lung.In summary, obesity is a global burden that influences lung function. Future research should reveal if obesity, and in particular visceral fat, causes lung inflammation and thereby impairs lung function.Large randomized trials are necessary to establish the effect of vitamin D therapy on infections in vitamin deficient patients. Show less
This thesis is a combination of traumatic and non-traumatic events in the abdomen, and the optimization of treatment in both entities. The first part describes the very prevalent infection caused... Show moreThis thesis is a combination of traumatic and non-traumatic events in the abdomen, and the optimization of treatment in both entities. The first part describes the very prevalent infection caused by the bacterium Clostridium difficile. The colitis caused by this infection can be severe and complicated, resulting in high morbidity and mortality. The studies show that by early diagnosis, improved logistics and conservative antibiotic management, treatment can be optimized. In the second part of the thesis, severe trauma to the abdomen is described. In severe renal and liver injuries, as well as in injuries to the pancreatoduodenal complex we show that a more conservative approach is possible, instead of an invasive, surgical treatment. If the clinical situation permits it, even the most severe injuries to the abdomen can be managed without an operation. Additionally we conclude that improved logistics around this specific patient population will be necessary in further optimizing outcomes. Show less
