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Introduction: Maternal nutritional and vitamin status during pregnancy may have long-term effects on offspring health and disease. The aim of this study was to examine the associations between maternal vitamin A and D status in pregnancy and offspring bone mineral content (BMC) at nine years of age. Methods: This is a post-hoc study of a randomized control trial including 855 pregnant women from two Norwegian cities; Trondheim and Stavanger. The women were randomized into an exercise intervention or standard antenatal care. Mother and child pairs for the present study were recruited from those still living in Trondheim after 8-10 years. Serum vitamin A (retinol) and vitamin D (25(OH)D) were measured in the 2nd and 3rd trimesters of pregnancy, and active vitamin D (1,25(OH)2D) in serum was measured in a subgroup. Spine BMC and trabecular bone score were measured in the children at nine years of age. Associations were analyzed with linear regression models. Results: A total of 119 mother and child pairs were included in the analyses. Vitamin A insufficiency (retinol< 1.05 µmol/L) and vitamin D deficiency (25(OH)D< 50 mmol/L) increased from ~7% to ~43% and from ~28% to ~33%, respectively, from the 2nd to the 3rd trimester. An increase in serum 1,25(OH)2D from the 2nd to the 3rd trimester was observed in the subgroup. There was a negative association between serum retinol in the 2nd trimester and spine BMC in the boys, but not in the girls, when adjusted for maternal and child confounders. No other associations between maternal serum vitamin A or D and BMC in the children were found. Conclusion: We observed a high prevalence of vitamin A insufficiency and vitamin D deficiency during pregnancy. A negative association between mid-pregnancy vitamin A status and spine BMC was observed in boys, but not girls, while no associations were found between maternal vitamin D status and child BMC. The implications of optimal vitamin A and D status in pregnancy for offspring bone health, remains a subject for further investigations.
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Densidad Ósea , Segundo Trimestre del Embarazo , Tercer Trimestre del Embarazo , Vitamina A , Vitamina D , Humanos , Femenino , Embarazo , Vitamina A/sangre , Vitamina D/sangre , Tercer Trimestre del Embarazo/sangre , Masculino , Niño , Adulto , Segundo Trimestre del Embarazo/sangre , Deficiencia de Vitamina D/epidemiología , Deficiencia de Vitamina D/sangre , Deficiencia de Vitamina A/sangre , Deficiencia de Vitamina A/epidemiología , Noruega/epidemiología , Fenómenos Fisiologicos Nutricionales Maternos , Efectos Tardíos de la Exposición Prenatal/sangre , Efectos Tardíos de la Exposición Prenatal/epidemiologíaRESUMEN
BACKGROUND: Research focusing on the association between serum vitamin D and oral health outcomes in children, such as dental caries and molar incisor hypomineralisation (MIH), shows inconsistent results. Previous studies have predominantly investigated dental caries and MIH as dichotomized outcomes, which limits the information on their distribution. In addition, the methods used for analysing serum vitamin D have varied. The present study aimed to investigate potential associations between serum vitamin D status measured by Liquid Chromatography with Tandem Mass Spectrometry (LC-MS/MS) and the prevalence, as well as the number of teeth, affected by dental caries or MIH among 7-9-year-old Norwegian children. METHODS: The study had a cross-sectional design and included 101 children aged 7-9 years. Serum 25-hydroxyvitamin D (25(OH)D) was measured and included as continuous (per 25 nmol/l) and categorised (insufficient (< 50 nmol/l) and sufficient (≥50 nmol/l)) exposure variables. Adjusted negative binomial hurdle models were used to investigate the potential associations between serum vitamin D and the oral health outcomes (dental caries and MIH) adjusted for sex, age, body mass index, season of blood draw, and mother's educational level. RESULTS: Of the 101 children in the total sample, 27% had insufficient vitamin D levels (< 50 nmol/l). The descriptive analysis indicated that the children with insufficient vitamin D levels had a higher prevalence (33.3%) and a higher number of teeth affected by dental caries (mean (SD) = 0.7 (1.4)), compared to children with sufficient levels of vitamin D (21.6% and mean (SD) = 0.4 (0.8), respectively). The same holds for MIH, with a higher prevalence (38.5%) and a higher number of teeth affected (mean (SD) = 1.2 (2.3)), compared to children with sufficient levels of vitamin D (30.1% and mean (SD) = 0.8 (1.6), respectively). However, in the adjusted hurdle model analysis, neither the prevalence or number of teeth affected by caries or MIH showed statistically significant associations with having insufficient or lower vitamin D levels. CONCLUSIONS: Vitamin D status was not significantly associated with the prevalence and number of teeth affected by caries and MIH among the participating children. Large prospective studies with multiple serum vitamin D measurements and oral examinations throughout childhood are warranted to elucidate the relationship.
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Caries Dental , Hipomineralización Molar , Niño , Humanos , Estudios Transversales , Cromatografía Liquida , Caries Dental/epidemiología , Estudios Prospectivos , Espectrometría de Masas en Tándem , Vitamina D , VitaminasRESUMEN
BACKGROUND: Studies on body composition in preterm very low birth weight (VLBW < 1500 g) survivors are inconsistent and trajectories later in life unknown. We assessed body composition and its change from young to mid-adulthood in VLBW adults. METHODS: We studied 137 VLBW adults and 158 term-born controls from two birth cohorts in Finland and Norway at mean age 36 years. Body composition was assessed by 8-polar bioelectrical impedance. We compared results with dual-energy x-ray absorptiometry measurements at 24 years. RESULTS: In mid-adulthood, VLBW women and men were shorter than controls. Fat percentage (mean difference in women 1.1%; 95% CI, -1.5% to 3.5%, men 0.8%; -2.0% to 3.6%) and BMI were similar. VLBW women had 2.9 (0.9 to 4.8) kg and VLBW men 5.3 (2.7 to 8.1) kg lower lean body mass than controls, mostly attributable to shorter height. Between young and mid-adulthood, both groups gained fat and lean body mass (p for interaction VLBW x age>0.3). CONCLUSION: Compared with term-born controls, VLBW adults had similar body fat percentage but lower lean body mass, largely explained by their shorter height. This could contribute to lower insulin sensitivity and muscular fitness previously found in VLBW survivors and predispose to functional limitations with increasing age. IMPACT: In mid-adulthood, individuals born preterm with very low birth weight had similar body fat percentage but lower lean body mass than those born at term. This was largely explained by their shorter height. First study to report longitudinal assessments of body size and composition from young to mid-adulthood in very low birth weight adults. Lower lean body mass in very low birth weight adults could contribute to lower insulin sensitivity and muscular fitness and lead to earlier functional limitations with increasing age.
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In vitro models of primary human osteocytes embedded in natural mineralized matrix without artificial scaffolds are lacking. We have established cell culture conditions that favored the natural 3D orientation of the bone cells and stimulated the cascade of signaling needed for primary human osteoblasts to differentiate into osteocytes with the characteristically phenotypical dendritic network between cells. Primary human osteoblasts cultured in a 3D rotating bioreactor and incubated with a combination of vitamins A, C, and D for up to 21 days produced osteospheres resembling native bone. Osteocyte-like cells were identified as entrapped, stellate-shaped cells interconnected through canaliculi embedded in a structured, mineralized, collagen matrix. These cells expressed late osteoblast and osteocyte markers such as osteocalcin (OCN), podoplanin (E11), dentin matrix acidic phosphoprotein 1 (DMP1), and sclerostin (SOST). Organized collagen fibrils, observed associated with the cell hydroxyapatite (HAp) crystals, were found throughout the spheroid and in between the collagen fibrils. In addition to osteocyte-like cells, the spheroids consisted of osteoblasts at various differentiation stages surrounded by a rim of cells resembling lining cells. This resemblance to native bone indicates a model system with potential for studying osteocyte-like cell differentiation, cross-talk between bone cells, and the mineralization process in a bonelike structure in vitro without artificial scaffolds. In addition, natural extracellular matrix may allow for the study of tissue-specific biochemical, biophysical, and mechanical properties. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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OBJECTIVES: Positive effects of irisin on osteogenic differentiation of periodontal ligament (PDL) cells have been identified previously, this study aims to examine its effect on orthodontic tooth movement (OTM) in vivo. MATERIALS AND METHODS: The maxillary right first molars of male Wistar rats (n = 21) were moved mesially for 14 days, with submucosal injection of two dosages of irisin (0.1 or 1 µg) or phosphate-buffered saline (control) every third day. OTM was recorded by feeler gauge and micro-computed tomography (µCT). Alveolar bone and root volume were analysed using µCT, and plasma irisin levels by ELISA. Histological characteristics of PDL tissues were examined, and the expression of collagen type I, periostin, osteocalcin (OCN), von Willebrand factor (vWF) and fibronectin type III domain-containing protein 5 (FNDC5) in PDL was evaluated by immunofluorescence staining. RESULTS: Repeated 1 µg irisin injections suppressed OTM on days 6, 9, and 12. No significant differences were observed in OTM in the 0.1 µg irisin group, or in bone morphometric parameters, root volume or plasma irisin, compared to control. Resorption lacunae and hyalinization were found at the PDL-bone interface on the compression side in the control, whereas they were scarce after irisin administration. The expression of collagen type I, periostin, OCN, vWF, and FNDC5 in PDL was enhanced by irisin administration. LIMITATIONS: The feeler gauge method may overestimate OTM. CONCLUSIONS: Submucosal irisin injection reduced OTM by enhancing osteogenic potential of PDL, and this effect was more significant on the compression side.
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Fibronectinas , Osteogénesis , Ratas , Masculino , Animales , Ratas Wistar , Fibronectinas/farmacología , Fibronectinas/metabolismo , Ligamento Periodontal/metabolismo , Técnicas de Movimiento Dental/métodos , Microtomografía por Rayos X/métodos , Colágeno Tipo I , Factor de von Willebrand/metabolismo , OsteoclastosRESUMEN
Introduction: There is increasing evidence that the in utero environment affects the health and disease risk of offspring throughout their lives. The long-term effect of maternal hyperglycaemia on offspring glucose metabolism is of interest in a public health perspective. The aim of this study was to examine the association between in utero exposure to maternal glycaemia and offspring glucose metabolism. Methods: Mother-child pairs were recruited from an RCT to prevent gestational diabetes mellitus where 855 healthy pregnant women were randomised to exercise or standard antenatal care. The original RCT detected no group differences in gestational diabetes mellitus prevalence or insulin resistance. The two groups were analysed as one group in the present study. Maternal glucose levels were assessed after 2-hour 75-gram oral glucose tolerance tests in pregnancy week ~34. Offspring outcomes were evaluated at ~9 years of age and included fasting glucose and homeostatic model assessment of insulin resistance. Multivariable regression models were performed, controlling for potential hereditary and lifestyle confounding factors. Results: Complete data were available for 105 mother-child pairs. The regression analysis showed a positive association between maternal and offspring fasting glucose that was borderline significant (beta=0.18, 95% CI [-0.00027, 0.37], p=0.050). We did not find significant associations between maternal fasting glucose and offspring insulin resistance (beta=0.080, 95% CI [-0.087, 0.25], p=0.34), or between maternal 2-hour glucose and offspring fasting glucose (beta=0.016, 95% CI [-0.038, 0.070], p=0.56) or insulin resistance (beta=0.017, 95% CI [-0.032, 0.065], p=0.49). Conclusions: Assessing a homogeneous group of healthy mother-child pairs, we found a borderline significant positive association between maternal and offspring fasting glucose, which persisted after adjustment for potential hereditary and lifestyle confounding factors. Our findings support other similar studies and highlight that improving the metabolic health of pregnant women, and women in childbearing age, should remain a key public health priority. Clinical trial registration: ClinicalTrials.gov, identifier NCT00476567.
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Diabetes Gestacional , Resistencia a la Insulina , Embarazo , Humanos , Femenino , Diabetes Gestacional/epidemiología , Estudios de Seguimiento , Glucosa , MadresRESUMEN
Context: Exercise is recognized as an important strategy to prevent bone loss, but its acute effects on bone turnover markers (BTMs) and related markers remain uncertain. Objective: To assess the acute effects of two different exercise modes on BTMs and related markers in young adults of both sexes and elderly men. Design Setting Participants: This was a three-group crossover within-subjects design study with a total of 53 participants-19 young women (aged 22-30), 20 young men (aged 21-30 years), and 14 elderly men (aged 63-74 years)-performing two different exercise sessions [strength training (ST) and high-intensity interval training (HIIT)] separated by 2 weeks, in a supervised laboratory setting. Main Outcome Measures: Plasma volume-corrected serum measurements of the BTMs C-terminal telopeptide of type 1 collagen (CTX-I) and procollagen of type 1 N-terminal propeptide (P1NP), total osteocalcin (OC), sclerostin, and lipocalin-2 (LCN2) at baseline, immediately after, and 3 and 24 h after each of the two exercise modes were performed. Results and Conclusion: Analyses revealed sex- and age-dependent differences in BTMs and related bone markers at baseline and time-, sex-, and age-dependent differences in response to exercise. No differences between exercise modes were observed for BTM response except for sclerostin in young men and LCN2 in elderly men. An acute, transient, and uniform increase in P1NP/CTX-1 ratio was found in young participants, demonstrating that beneficial skeletal effects on bone metabolism can be attained through both aerobic endurance and resistance exercise, although this effect seems to be attenuated with age. The acute effects of exercise on bone-related biomarkers were generally blunted after 24 h, suggesting that persistent alterations following prolonged exercise interventions should be assessed at later time points.
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Enfermedades Óseas Metabólicas , Entrenamiento Aeróbico , Anciano , Remodelación Ósea/fisiología , Femenino , Humanos , Masculino , Osteocalcina , Procolágeno , Adulto JovenRESUMEN
Given the scarcity of data on diabetes prevalence and associated risk factors among women in rural Nepal, we aimed to examine this, using glycated hemoglobin (HbA1c) as a diagnostic tool. A cross-sectional survey addressing reproductive health and non-communicable diseases was conducted in 2012-2013 among non-pregnant, married women in Bolde, a rural district of Nepal. HbA1c ≥ 6.5% (48 mmol/mol) was used as diagnostic criterion for diabetes, a cut-off of 7.0% (53 mmol/mol) was used to increase the specificity. HbA1c was measured in 757 women (17-86 years). The prevalence of diabetes and prediabetes was 13.5% and 38.5%, respectively. When using 7.0% as a cut-off, the prevalence of diabetes was 5.8%. Aging, intake of instant noodles and milk and vegetarian food (ns) were associated with increased risk for diabetes. Waist circumference was higher among women with diabetes, although not significant. The women were uneducated (87.6%), and only 12% had heard about diabetes. In conclusion, we observed a higher prevalence of diabetes and prediabetes than anticipated among rural, Nepalese women. The increased risk was mainly attributed to dietary factors. In contrast to most previous studies in Nepal, we used HbA1c as diagnostic criterion.
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Diabetes Mellitus , Estado Prediabético , Glucemia , Estudios Transversales , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/epidemiología , Femenino , Hemoglobina Glucada/análisis , Humanos , Nepal/epidemiología , Estado Prediabético/diagnóstico , Estado Prediabético/epidemiología , Prevalencia , Factores de RiesgoRESUMEN
Hypovitaminosis D is prevalent worldwide, and especially in South-Asia. According to the Institute of Medicine (IOM), 25(OH)D levels below 30 nmol/L are defined as vitamin D deficiency (VDD) and levels between 30−50 nmol/L as insufficiency (VDI). Besides its role in calcium homeostasis, it has been postulated that vitamin D is involved in metabolic syndrome. Given the scarcity of data on vitamin D status in Nepal, we aimed to examine the prevalence of VDD and VDI, as well as the determinants and association with metabolic parameters (lipids, HbA1c), in a cohort of women in rural Nepal. Altogether, 733 women 48.5 ± 11.7 years of age were included. VDD and VDI were observed in 6.3 and 42.4% of the participants, respectively, and the prevalence increased by age. Women reporting intake of milk and eggs > 2 times weekly had higher 25(OH)D levels than those reporting intake < 2 times weekly. Women with vitamin D levels < 50 nmol/L displayed higher levels of cholesterol, LDL-cholesterol, triglycerides, and HbA1c. Additionally, a regression analysis showed a significant association between hypovitaminosis D, dyslipidemia, and HbA1c elevation. In conclusion, VDI was prevalent and increased with age. Milk and egg intake > 2 times weekly seemed to decrease the risk of VDI. Moreover, hypovitaminosis D was associated with an adverse metabolic profile.
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Raquitismo , Deficiencia de Vitamina D , Femenino , Hemoglobina Glucada/análisis , Humanos , Metaboloma , Nepal/epidemiología , Prevalencia , Vitamina D/análisis , Deficiencia de Vitamina D/epidemiología , VitaminasRESUMEN
OBJECTIVE: Bisphosphonates like alendronate mainly exert their effects on osteoclasts. However, osteoblasts are also affected, but exposed to a much lower concentration in vivo than the osteoclasts. Given that the effects are dose-dependent, the intention of the study was to identify a therapeutically relevant concentration of alendronate for in vitro studies on osteoblasts. MATERIALS AND METHODS: Primary human osteoblasts were incubated with alendronate (5, 20 and 100 µM) for 1, 3, 7 and 14 days. Proliferation and viability were assessed, and the effects on cellular growth and function were evaluated by multianalyte profiling of selected proteins in cell culture media using the Luminex 200TM. RESULTS: The viability was not affected by any of the dosages. Exposure to 5 µM alendronate had a neutral effect on osteoblast proliferation, and on secretion of osteogenic and inflammatory markers, while enhancing synthesis of a marker of angiogenesis. 20 µM alendronate induced a decline in proliferation and affected angiogenic and osteogenic biomarkers adversely. 100 µM alendronate reduced proliferation dramatically, and this dosage was excluded from further experiments. CONCLUSION: A concentration of 5 µM alendronate exerted effects on human osteoblasts that may translate to those observed in vivo and could therefore be relevant for in vitro studies.
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Alendronato , Osteoblastos , Humanos , Alendronato/farmacología , Difosfonatos/farmacología , Osteoclastos , Osteogénesis , Células CultivadasRESUMEN
OBJECTIVE: Type 1 diabetes (T1D) is associated with substantial fracture risk. Bone mineral density (BMD) is, however, only modestly reduced, suggesting impaired bone microarchitecture and/or bone material properties. Yet, the skeletal abnormalities have not been uncovered. Men with T1D seem to experience a more pronounced bone loss than their female counterparts. Hence, we aimed to examine different aspects of bone quality in men with T1D. DESIGN AND METHODS: In this cross-sectional study, men with T1D and healthy male controls were enrolled. BMD (femoral neck, total hip, lumbar spine, whole body) and spine trabecular bone score (TBS) were measured by dual x-ray absorptiometry, and bone material strength index (BMSi) was measured by in vivo impact microindentation. HbA1c and bone turnover markers were analyzed. RESULTS: Altogether, 33 men with T1D (43 ± 12 years) and 28 healthy male controls (42 ± 12 years) were included. Subjects with T1D exhibited lower whole-body BMD than controls (P = 0.04). TBS and BMSi were attenuated in men with T1D vs controls (P = 0.016 and P = 0.004, respectively), and T1D subjects also had a lower bone turnover. The bone parameters did not differ between subjects with or without diabetic complications. Duration of disease correlated negatively with femoral neck BMD but not with TBS or BMSi. CONCLUSIONS: This study revealed compromised bone material strength and microarchitecture in men with T1D. Moreover, our data confirm previous studies which found a modest decrease in BMD and low bone turnover in subjects with T1D. Accordingly, bone should be recognized as a target of diabetic complications.
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Patients with gastroesophageal reflux disease (GERD) are routinely treated with proton pump inhibitors (PPIs), despite many reports of increased fracture risk associated with PPI use. Notably, the skeletal properties in patients with GERD prior to PPI therapy have not been addressed. We hypothesized that PPI-naïve GERD patients have bone impairment, and that short-term treatment with PPI has minimal skeletal effects. To test this, 17 (12 men/5 women) GERD patients age 32-73 years, not previously exposed to PPI, and 17 age- and sex-matched controls were enrolled from September 2010 to December 2012. Bone mineral density (BMD) at lumbar spine, femoral neck, total hip, and trabecular bone score (TBS) at the lumbar spine, a marker of bone microarchitecture, were measured by dual X-ray absorptiometry. Markers of bone turnover and calcium homeostasis, and gastric hormones were analyzed. The same parameters were measured after three months of treatment with the PPI pantoprazole. The GERD patients displayed a significantly lower TBS at baseline than controls (1.31 ± 0.11 vs. 1.43 ± 0.07, p = 0.0006). Total hip and femoral neck BMD were lower in patients compared to controls, however, not significantly (p = 0.09 and 0.12, respectively). CTX was non-significantly higher in GERD patients at baseline (p = 0.11). After three months, changes in BMD, TBS and CTX did not differ between the groups. In conclusion, this is the first report demonstrating compromised bone quality and inferior BMD in PPI-naïve GERD patients. Treatment with pantoprazole did not influence bone parameters, indicating that short-term use with this PPI is safe for the skeleton.
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OBJECTIVE: Due to gastrointestinal side effects of oral bisphosphonates (BPs), proton pump inhibitors (PPIs) are often prescribed. PPIs may enhance the risk of osteonecrosis of the jaw, a rare side effect of BPs. Therefore, the objective of this study was to evaluate the effects of the oral BP alendronate (ALN) and the PPI omeprazole (OME) alone and in combination on primary human osteoblasts and gingival fibroblasts in vitro. METHODS: Human gingival fibroblasts and normal human osteoblasts were incubated with either 5 µM of ALN or 1 µM of OME, or ALN + OME for 1, 3, 7 or 14 days. Effect on viability was evaluated by the lactate dehydrogenase activity in the medium and on proliferation by quantifying 3H-thymidin incorporation. Multianalyte profiling of proteins in cell culture media was performed using the Luminex 200TM system to assess the effect on selected bone markers and cytokines. RESULTS: The proliferation of osteoblasts and fibroblasts was reduced upon exposure to ALN + OME. ALN induced an early, temporary rise in markers of inflammation, and OME and ALN + OME promoted a transient decline. An initial increase in IL-13 occurred after exposure to all three options, whereas ALN + OME promoted IL-8 release after 7 days. OME and ALN + OME promoted a transient reduction in vascular endothelial growth factor (VEGF) from osteoblasts, whereas ALN and ALN + OME induced a late rise in VEGF from fibroblasts. Osteoprotegerin release was enhanced by ALN and suppressed by OME and ALN + OME. CONCLUSIONS: ALN + OME seemed to exaggerate the negative effects of each drug alone on human osteoblasts and gingival fibroblasts. The anti-proliferative effects, modulation of inflammation and impairment of angiogenesis, may induce unfavorable conditions in periodontal tissue facilitating development of osteonecrosis.
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Rotational culture promotes primary human osteoblasts (hOBs) to form three-dimensional (3D) multicellular spheroids with bone tissue-like structure without any scaffolding material. Cell-based bone models enable us to investigate the effect of different agents on the mechanical strength of bone. Given that low dietary intake of both vitamin D and K is negatively associated with fracture risk, we aimed to assess the effect of these vitamins in this system. Osteospheres of hOBs were generated with menaquinone-4 (MK-4; 10µM) and 25-hydroxyvitamin D3 [25(OH)D3; 0.01µM], alone and in combination, or without vitamins. The mechanical properties were tested by nanoindentation using a flat-punch compression method, and the mineralized extracellular bone matrix was characterized by microscopy. The in vitro response of hOBs to MK-4 and 25(OH)D3 was further evaluated in two-dimensional (2D) cultures and in the 3D bone constructs applying gene expression analysis and multiplex immunoassays. Mechanical testing revealed that 25(OH)D3 induced a stiffer and MK-4 a softer or more flexible osteosphere compared with control. Combined vitamin conditions induced the same flexibility as MK-4 alone. Enhanced levels of periostin (p < 0.001) and altered distribution of collagen type I (COL-1) were found in osteospheres supplemented with MK-4. In contrast, 25(OH)D3 reduced COL-1, both at the mRNA and protein levels, increased alkaline phosphatase, and stimulated mineral deposition in the osteospheres. With the two vitamins in combination, enhanced gene expression of periostin and COL-1 was seen, as well as extended osteoid formation into the central region and increased mineral deposition all over the area. Moreover, we observed enhanced levels of osteocalcin in 2D and osteopontin in 3D cultures exposed to 25(OH)D3 alone and combined with MK-4. In conclusion, the two vitamins seem to affect bone mechanical properties differently: vitamin D enhancing stiffness and K2 conveying flexibility to bone. These effects may translate to increased fracture resistance in vivo. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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Proton pump inhibitor use is associated with an increased risk of gastric cancer, which may be mediated by hypergastrinemia. Spasmolytic polypeptide-expression metaplasia (SPEM) has been proposed as a precursor of gastric cancer. We have examined the effects of the gastrin receptor antagonist netazepide (NTZ) or vehicle on the gastric corpus mucosa of H+/K+ATPase beta subunit knockout (KO) and wild-type (WT) mice. The gastric corpus was evaluated by histopathology, immunohistochemistry (IHC), in situ hybridization (ISH) and whole-genome gene expression analysis, focusing on markers of SPEM and neuroendocrine (NE) cells. KO mice had pronounced hypertrophy, intra- and submucosal cysts and extensive expression of SPEM and NE cell markers in the gastric corpus, but not in the antrum. Numerous SPEM-related genes were upregulated in KO mice compared to WT mice. NTZ reduced hypertrophia, cysts, inflammation and NE hyperplasia. However, NTZ neither affected expression of SPEM markers nor of SPEM-related genes. In conclusion, NTZ prevented mucosal hypertrophy, cyst formation and NE cell hyperplasia but did not affect SPEM. The presence of SPEM seems unrelated to the changes caused by hypergastrinemia in this animal model.
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Benzodiazepinonas/administración & dosificación , Mucosa Gástrica/patología , ATPasa Intercambiadora de Hidrógeno-Potásio/genética , Péptidos y Proteínas de Señalización Intercelular/genética , Células Neuroendocrinas/patología , Compuestos de Fenilurea/administración & dosificación , Animales , Benzodiazepinonas/farmacología , Femenino , Perfilación de la Expresión Génica/métodos , Regulación de la Expresión Génica/efectos de los fármacos , ATPasa Intercambiadora de Hidrógeno-Potásio/metabolismo , Humanos , Hiperplasia/prevención & control , Hibridación in Situ , Inyecciones Subcutáneas , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Masculino , Metaplasia , Ratones , Ratones Noqueados , Compuestos de Fenilurea/farmacología , Secuenciación del ExomaRESUMEN
The balance between bone resorption and formation may be assessed by measurement of bone turnover markers (BTMs), like carboxyl-terminal cross-linked telopeptide of type 1 collagen (CTX-1) and procollagen type 1 amino-terminal propeptide (P1NP). Smoking has been shown to influence bone turnover and to reduce bone mass density (BMD), the exact mechanism for this is, however, not settled. In this post-hoc study including 406 subjects (mean age 51.9 years), we aimed to study the impact of smoking on bone turnover. Moreover, we wanted to assess the inter-correlation between substances regulating bone metabolism and BTMs, as well as tracking over time. BMD measurements and serum analyses of CTX-1, P1NP, osteoprotegerin (OPG), receptor activator of nuclear factor ĸB ligand (RANKL), Dickkopf-1 (DKK1), sclerostin, tumor necrosis factor-α (TNF-α), and leptin were performed. Repeated serum measurements were made in 195 subjects after four months. Adjustments were made for sex, age, body mass index (BMI), smoking status, insulin resistance, serum calcium, parathyroid hormone, 25-hydroxyvitamin D and creatinine. Smokers had higher levels of DKK1 and OPG, and lower levels of RANKL, as reflected in lower BTMs and BMD compared to non-smokers. There were strong and predominantly positive inter-correlations between BTMs and the other substances, and there was a high degree of tracking with Spearman's rho from 0.72 to 0.92 (P < 0.001) between measurements four months apart. In conclusion, smokers exhibited higher levels of DKK1 and OPG and a lower bone turnover than did non-smokers. The strong inter-correlations between the serum parameters illustrate the coupling between bone resorption and formation and crosstalk between cells.
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Remodelación Ósea , Fumar , Adulto , Biomarcadores/sangre , Densidad Ósea , Femenino , Humanos , Péptidos y Proteínas de Señalización Intercelular/sangre , Masculino , Persona de Mediana Edad , Osteoprotegerina/sangre , Hormona Paratiroidea/sangre , Fragmentos de Péptidos/sangre , Procolágeno/sangre , Ligando RANK/sangre , Vitamina D/análogos & derivados , Vitamina D/sangreRESUMEN
BACKGROUND: Vitamin A and D deficiency is prevalent in pregnant women worldwide. Both vitamins are involved in fetal skeletal development. A positive association between maternal vitamin D levels and offspring bone mineral density (BMD) at adulthood has been observed. The impact of maternal vitamin A status in pregnancy on offspring peak bone mass remains unclear. METHOD AND FINDINGS: Forty-one mother-child pairs were recruited from a population-based prospective cohort study in Trondheim, Norway, where pregnant women were followed from gestational week 17. Their term-born infants were followed from birth (1986-88). Regression analyses were performed for vitamin A (retinol), 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)2D] in maternal serum (gestational weeks 17, 33, 37) and cord blood. Offspring BMD and spine trabecular bone score (TBS), a measure of bone quality, were analyzed by dual x-ray absorptiometry at 26 years. Average levels during pregnancy of retinol, 25(OH)D and 1,25(OH)2D were 1.66 (0.32) µmol/L, 59.0 (20.6) nmol/L, and 251.3 (62.4) pmol/L, respectively. 1,25(OH)2D levels were similar in those with 25(OH)D levels <30 and >75 nmol/L. After adjustment for maternal age, BMI, smoking, and education, and offspring birth weight, maternal serum retinol was positively associated with offspring spine BMD [mean change 30.8 (CI 7.6, 54.0) mg/cm2 per 0.2 µmol/L retinol], and with offspring TBS, although non-significant (p = 0.08). No associations were found between maternal 25(OH)D and 1,25(OH)2D levels and offspring bone parameters. Vitamin levels in cord blood were not associated with offspring BMD or TBS. CONCLUSIONS: This is the first study to show an association between maternal vitamin A status and offspring peak bone mass. Our findings may imply increase future risk for osteoporotic fracture in offspring of mothers with suboptimal vitamin A level. No associations were observed between 25(OH)D and 1,25(OH)2D and offspring BMD.
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Densidad Ósea/fisiología , Fracturas Osteoporóticas/epidemiología , Complicaciones del Embarazo/sangre , Efectos Tardíos de la Exposición Prenatal/epidemiología , Deficiencia de Vitamina A/sangre , Deficiencia de Vitamina D/sangre , Absorciometría de Fotón , Adulto , Femenino , Estudios de Seguimiento , Humanos , Masculino , Noruega , Fracturas Osteoporóticas/diagnóstico por imagen , Fracturas Osteoporóticas/fisiopatología , Embarazo , Efectos Tardíos de la Exposición Prenatal/diagnóstico por imagen , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Estudios Prospectivos , Medición de Riesgo , Factores de Riesgo , Vitamina A/sangre , Vitamina D/análogos & derivados , Vitamina D/sangreRESUMEN
In observational studies, vitamin D deficiency is a risk factor for low bone density and future fractures, whereas a causal relation has been difficult to show in randomized controlled trials (RCTs). Similarly, vitamin D deficiency has been associated with increased bone turnover, but RCTs with vitamin D have not shown conclusive effects. This could be due to inclusion of vitamin D sufficient subjects and low vitamin D doses. In the present study 399 subjects with mean baseline serum 25-hydroxyvitamin D (25(OH)D) 34.0â¯nmol/L completed a four months intervention with vitamin D3 20,000â¯IU per week versus placebo. Mean serum 25(OH)D increased to 89.0â¯nmol/L in the vitamin D group and decreased slightly in the placebo group. A small, but significant, decrease in the bone formation marker procollagen of type 1 amino-terminal propeptide (P1NP) was seen in the vitamin D group as compared to the placebo group (mean delta P1NP -1.2â¯pg/mL and 1.5â¯ng/mL, respectively, Pâ¯<â¯0.01). No significant effects were seen on serum carboxyl-terminal telopeptide of type 1 collagen (CTX-1), Dickkopf-1, sclerostin, tumor necrosis factor-alpha, osteoprotegerin, receptor activator of nuclear factor ĸB ligand, or leptin. Subgroup analyses on subjects with low baseline serum 25(OH)D did not yield additional, significant results. In subjects with high baseline serum parathyroid hormone (PTH)â¯>â¯6.5â¯pmol/L and post-intervention decrease in PTH, the decrease in P1NP was more pronounced, they also exhibited significantly reduced serum CTX-1 and increased serum sclerostin. In conclusion, supplementation with vitamin D appears to suppress bone turnover, possibly mediated by PTH reduction. Our findings need to be confirmed in even larger cohorts with vitamin D insufficient subjects.
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Remodelación Ósea , Suplementos Dietéticos , Deficiencia de Vitamina D/tratamiento farmacológico , Deficiencia de Vitamina D/fisiopatología , Vitamina D/uso terapéutico , Biomarcadores/metabolismo , Calcio/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Hormona Paratiroidea/sangre , Vitamina D/análogos & derivados , Vitamina D/sangreRESUMEN
BACKGROUND: Vitamin D insufficiency is common in pregnant women worldwide. Regular prenatal exercise is considered beneficial for maternal and fetal health. There is a knowledge gap regarding the impact of prenatal exercise on maternal vitamin D levels. The objective of this study was to investigate whether a prenatal exercise program influenced serum levels of total, free and bioavailable 25-hydroxyvitamin D (25(OH)D) and related parameters. This is a post hoc analysis of a randomized controlled trial with gestational diabetes as the primary outcome. METHODS: Healthy, pregnant women from two Norwegian cities (Trondheim and Stavanger) were randomly assigned to a 12-week moderate-intensity exercise program (Borg perceived rating scale 13-14) or standard prenatal care. The intervention group (n = 429) underwent exercise at least three times weekly; one supervised group training and two home based sessions. The controls (n = 426) received standard prenatal care, and exercising was not denied. Training diaries and group training was used to promote compliance and evaluate adherence. Serum levels of 25(OH)D, parathyroid hormone, calcium, phosphate, magnesium and vitamin D-binding protein were measured before (18-22 weeks' gestation) and after the intervention (32-36 weeks' gestation). Free and bioavailable 25(OH)D concentrations were calculated. Regression analysis of covariance (ANCOVA) was applied to assess the effect of the training regime on each substance with pre-intervention levels as covariates. In a second model, we also adjusted for study site and sampling month. Intention-to-treat principle was used. RESULTS: A total of 724 women completed the study. No between-group difference in serum 25(OH)D and related parameters was identified by ANCOVA using baseline serum levels as covariates. The second model revealed a between-group difference in levels of 25(OH)D (1.9, 95% CI 0.0 to 3.8 nmol/L; p = 0.048), free 25(OH)D (0.55, 95% CI 0.10 to 0.99 pmol/L; p = 0.017) and bioavailable 25(OH)D (0.15 95% CI 0.01 to 0.29 nmol/L; p = 0.036). No serious adverse events related to regular exercise were seen. CONCLUSION: This study, a post hoc analysis, indicates that exercise may affect vitamin D status positively, and emphasizes that women with uncomplicated pregnancies should be encouraged to perform regular exercise. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00476567 , registered May 22, 2007.
Asunto(s)
Terapia por Ejercicio/métodos , Ejercicio Físico/fisiología , Estado Nutricional , Atención Prenatal/métodos , Vitamina D/análogos & derivados , Adulto , Calcio/sangre , Proteínas de Unión al ADN/sangre , Femenino , Voluntarios Sanos , Humanos , Magnesio , Noruega , Hormona Paratiroidea/sangre , Fosfatos/sangre , Embarazo , Complicaciones del Embarazo/etiología , Factores de Transcripción/sangre , Vitamina D/sangre , Deficiencia de Vitamina D/etiologíaRESUMEN
Introduction: We have previously determined the prevalence of human papillomavirus (HPV) infection among women in rural Nepal. In the current study, we also wanted to examine the prevalence of and risk factors for other sexually transmitted infections (STIs) in the same population. Methods: Population-based study of nonpregnant women ≥ 15 years who were married or had a history of marriage in the past, residing in five rural villages in Nepal. Data on sociodemographic characteristics, reproductive history, and genitourinary symptoms were collected, and a gynecological examination was conducted. Cervical samples were analyzed by real-time PCR for Neisseria gonorrhoeae, Chlamydia trachomatis, and Trichomonas vaginalis and HPV, and a serum sample was analyzed for syphilis, hepatitis B virus (HBV) and HIV infection by serology. Results: Of 2416 eligible women, 62% participated. Trichomoniasis, Chlamydia trachomatis infection, HPV and HBV infection, and syphilis were detected in 5.4%, 0.8%, 14.3%, 0.3%, and 0.2% of the women. None had gonorrhea or HIV infection. Of those with genitourinary symptoms, 6.3% had a curable STI. Vaginal discharge classified as abnormal by gynecological examination, but not self-reported discharge, was significantly associated with laboratory diagnosis of a curable STI. Risk factors for trichomoniasis were reproductive age and high cast/ethnicity. Due to low prevalence, risk factors for other STIs could not be disclosed. Conclusion: We observed high prevalence of HPV infection followed by trichomoniasis, while other STIs were rare among women in rural Nepal. There was no association between genitourinary symptoms and laboratory-confirmed STIs.