Spontaneous preterm birth (SPTB) is the leading cause of neonatal death and morbidity worldwide. Both maternal and fetal genetic factors likely contribute to SPTB. We performed a genome-wide ...association study (GWAS) on a population of Finnish origin that included 247 infants with SPTB (gestational age GA < 36 weeks) and 419 term controls (GA 38-41 weeks). The strongest signal came within the gene encoding slit guidance ligand 2 (SLIT2; rs116461311, minor allele frequency 0.05, p = 1.6×10-6). Pathway analysis revealed the top-ranking pathway was axon guidance, which includes SLIT2. In 172 very preterm-born infants (GA <32 weeks), rs116461311 was clearly overrepresented (odds ratio 4.06, p = 1.55×10-7). SLIT2 variants were associated with SPTB in another European population that comprised 260 very preterm infants and 9,630 controls. To gain functional insight, we used immunohistochemistry to visualize SLIT2 and its receptor ROBO1 in placentas from spontaneous preterm and term births. Both SLIT2 and ROBO1 were located in villous and decidual trophoblasts of embryonic origin. Based on qRT-PCR, the mRNA levels of SLIT2 and ROBO1 were higher in the basal plate of SPTB placentas compared to those from term or elective preterm deliveries. In addition, in spontaneous term and preterm births, placental SLIT2 expression was correlated with variations in fetal growth. Knockdown of ROBO1 in trophoblast-derived HTR8/SVneo cells by siRNA indicated that it regulate expression of several pregnancy-specific beta-1-glycoprotein (PSG) genes and genes involved in inflammation. Our results show that the fetal SLIT2 variant and both SLIT2 and ROBO1 expression in placenta and trophoblast cells may be correlated with susceptibility to SPTB. SLIT2-ROBO1 signaling was linked with regulation of genes involved in inflammation, PSG genes, decidualization and fetal growth. We propose that this receptor-ligand couple is a component of the signaling network that promotes SPTB.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objectives
The aim was to investigate the severity of untreated dental caries among Nepalese schoolchildren and its association with their body mass index (BMI) using IOTF, WHO and Nepalese growth ...reference systems.
Methods
This school‐based clinical cross‐sectional study was conducted with three WHO index age groups (5‐ to 6‐, 12‐ and 15‐year‐olds) in 18 out of 75 districts of Nepal, selected using stratified random sampling. A total of 1135 schoolchildren were included in the study. A validated structured questionnaire was used to assess the children's oral hygiene practices and dietary habits. Clinical oral examinations investigated the status of untreated dental caries in primary and permanent teeth (dt/DT) along with its consequences (pufa/PUFA). Later, the grade of severity of untreated dental caries (GUDC) was determined using both dt/DT and pufa/PUFA. Height (cm), weight (kg), waist circumference (cm) and hip circumference (cm) were measured, and the body mass index (BMI), waist‐to‐hip ratio (WHR) and waist‐to‐height ratio (WHtR) were calculated. The findings were presented as proportions, and the chi‐square test was performed to compare differences between groups. Generalized linear mixed models with random effects assessed the association between the severity of untreated dental caries and the BMI.
Results
According to the IOTF, WHO and Nepalese growth reference systems, the overall proportions of children with a low BMI were 38.6%, 15.4% and 12.8%, and those with a high BMI were 7.9%, 4.6% and 8.4%, respectively. Untreated dental caries was common among the youngest age group and those with infrequent tooth brushing habits or frequent consumption of sweet bakery products, sweets or candy, or tea with sugar. Neither a low nor a high BMI was associated either with dt + DT or with pufa + PUFA, after adjusting for confounders. However, both a low and a high BMI (all three references) were associated with the severity of dental caries or GUDC.
Conclusion
Regardless of the growth reference system used, children with either low or high BMI may be at risk of developing untreated dental caries lesions and related consequences. Both underweight and overweight/obese and dental caries share common risk factors, mostly dietary. Preventive and intervention approaches/strategies such as behavioural and dietary modifications should be implemented to improve both children's oral health and their nutrition in Nepal.
Preterm birth (<37 weeks of gestation) is a major cause of neonatal death and morbidity. Up to 40% of the variation in timing of birth results from genetic factors, mostly due to the maternal genome.
...We conducted a genome-wide meta-analysis of gestational duration and spontaneous preterm birth in 68,732 and 98,370 European mothers, respectively.
The meta-analysis detected 15 loci associated with gestational duration, and four loci associated with preterm birth. Seven of the associated loci were novel. The loci mapped to several biologically plausible genes, for example HAND2 whose expression was previously shown to decrease during gestation, associated with gestational duration, and GC (Vitamin D-binding protein), associated with preterm birth. Downstream in silico-analysis suggested regulatory roles as underlying mechanisms for the associated loci. LD score regression found birth weight measures as the most strongly correlated traits, highlighting the unique nature of spontaneous preterm birth phenotype. Tissue expression and colocalization analysis revealed reproductive tissues and immune cell types as the most relevant sites of action.
We report novel genetic risk loci that associate with preterm birth or gestational duration, and reproduce findings from previous genome-wide association studies. Altogether, our findings provide new insight into the genetic background of preterm birth. Better characterization of the causal genetic mechanisms will be important to public health as it could suggest new strategies to treat and prevent preterm birth.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Purpose
Survivors of childhood brain tumors (BT) are at high risk for long-term physical and psychological sequelae. Still, knowledge about health-related quality of life (HRQL) and associated ...factors in this population is sparse. This study investigated HRQL and its predictors in long-term survivors of childhood BT.
Methods
Survivors of childhood BT (mean age = 28.1 years, SD = 6.8,
n
= 60) underwent clinical examination and neurocognitive examination, and completed self-rating questionnaires assessing HRQL (RAND-36) and depressive symptoms (Beck Depression Inventory-II). Socio-demographic information was gathered via a questionnaire. Tumor- and treatment-related information was collected from medical records. Control group data were collected from age-matched controls (
n
= 146) without a history of cancer, randomly selected from the local population registry. Multiple linear regression models were used to investigate predictors of HRQL; separate models were fitted for each domain of the RAND-36.
Results
Male survivors (mean age = 27.0, SD = 6.0,
n
= 39) reported significantly lower HRQL than male controls in the domains of physical functioning, general health, vitality, social functioning, and role limitations-emotional. Female survivors (mean age = 30.2 years, SD = 7.6,
n
= 21) reported comparable levels as female controls in all domains except physical functioning. A higher burden of late effects, not working/studying, being diagnosed with BT during adolescence, and reporting current depressive symptoms were significant predictors of lower HRQL.
Conclusion
Our results highlight that male survivors of childhood BT are at particular risk of impaired HRQL. Also, results point to the close relation between symptoms of depression and impaired HRQL in survivors of childhood BT which should be acknowledged by long-term follow-up care.
Preterm birth is defined as live birth before 37 completed weeks of pregnancy, and it is a major problem worldwide. The molecular mechanisms that lead to onset of spontaneous preterm birth are ...incompletely understood. Prediction and evaluation of the risk of preterm birth is challenging as there is a lack of accurate biomarkers. In this study, our aim was to identify placental proteins that associate with spontaneous preterm birth.
We analyzed the proteomes from placentas to identify proteins that associate with both gestational age and spontaneous labor. Next, rare and potentially damaging gene variants of the identified protein candidates were sought for from our whole exome sequencing data. Further experiments we performed on placental samples and placenta-associated cells to explore the location and function of the spontaneous preterm labor-associated proteins in placentas.
Exome sequencing data revealed rare damaging variants in SERPINA1 in families with recurrent spontaneous preterm deliveries. Protein and mRNA levels of alpha-1 antitrypsin/SERPINA1 from the maternal side of the placenta were downregulated in spontaneous preterm births. Alpha-1 antitrypsin was expressed by villous trophoblasts in the placenta, and immunoelectron microscopy showed localization in decidual fibrinoid deposits in association with specific extracellular proteins. siRNA knockdown in trophoblast-derived HTR8/SVneo cells revealed that SERPINA1 had a marked effect on regulation of the actin cytoskeleton pathway, Slit-Robo signaling, and extracellular matrix organization.
Alpha-1 antitrypsin is a protease inhibitor. We propose that loss of the protease inhibition effects of alpha-1 antitrypsin renders structures critical to maintaining pregnancy susceptible to proteases and inflammatory activation. This may lead to spontaneous premature birth.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
MicroRNAs (miRNAs) are important regulators of gene expression, and their expression is associated with many physiological conditions. Here, we investigated potential associations between expression ...levels of miRNAs in human placenta and the onset of spontaneous term birth. Using RNA sequencing, we identified 54 miRNAs differentially expressed during spontaneous term labor compared to elective term births. Expression levels of 23 miRNAs were upregulated, whereas 31 were downregulated at least 1.5-fold. The upregulated miRNA miR-371a-5p putatively targets CPPED1, expression of which decreases during spontaneous birth. We used a luciferase reporter-based assay to test whether a miR-371a-5p mimic affected translation when it bound to the 3' untranslated region of CPPED1. In this setting, the miR-371a-5p mimic resulted in lower luciferase activity, which suggests that miR-371a-5p regulates levels of CPPED1. In conclusion, inversely correlated levels of miR-371a-5p and CPPED1 suggest a role for both in spontaneous delivery.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Purpose Growth failure is common in radiotherapy-treated long-term survivors of pediatric brain tumors, but studies on longitudinal growth in this patient group are lacking. Here, the aim was to ...assess the changes in growth patterns before and after brain tumor diagnosis, the adult height, and the risk factors for compromised growth. The incidence and treatment practices of growth hormone deficiency were analyzed. Methods A cohort of 73 survivors of childhood brain tumor (median age 27.2 years, range 16.2 to 43.8 years) was studied after a median follow-up period of 20.4 years from diagnosis (IQR 14.9 to 22.9 years). Patients were treated in five university hospitals in Finland between 1970 and 2008. Growth curves, final height, and patient- and disease-related risk factors for compromised growth during different growth periods were analyzed. Laboratory analyses for IGF-1 and IGFBP-3 were performed at the follow-up. Results Growth failure was evident at diagnosis, with a mean height decline of -0.6 SDS (standard deviation score) from birth (95% CI -1.15 to -0.05). Mean height SDS decline after the diagnosis was -1.09 SDS (95%CI -1.51 to -0.66). At follow-up, 37% of the study subjects (27/73) had true short stature (height < -2 SDS). The mean height deficit corrected for target height was -1.9 SDS (95% CI -1.45 to -2.40). Growth failure was associated with the age at diagnosis, corticosteroid dose, radiotherapy modality and mean dose of irradiation in the thalamic area. Low IGF-1 level (below -2.0 SDS) was found in 32% (23/72), and untreated growth hormone deficiency in 40% (29/72) of the subjects. Conclusion Longitudinal growth impairment was common in radiotherapy-treated survivors of childhood brain tumor, resulting in compromised adult height. Loss of growth potential was evident already at diagnosis and further accelerated by the treatments. At young adulthood, unrecognized growth hormone deficiency was common.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Purpose
Populations living in the Nordic countries are at high risk for vitamin D (VitD) deficiency or insufficiency. To reduce the risk, nationwide interventions based on food fortification and ...supplementation are being implemented. However, there is limited evidence about the impact of such public health campaigns on target populations.
Methods
We studied an unselected sample of 3650 participants (56.2% females) from the longitudinal Northern Finland Birth Cohort 1966 with repeated measures of serum 25-hydroxyvitamin D 25(OH)D at ages 31 (1997) and 46 (2012–2013). Timepoints corresponded to the period before and during the food fortification. We examined the effect of VitD intake from the diet and supplementation, body mass index and previous 25(OH)D concentration on 25(OH)D concentration at 46 years using a multivariable linear regression analysis. A 25(OH)D
z
score adjusted for sex, season, latitude and technical effect was used in the analysis.
Results
We observed an increase of 10.6 nmol/L in 25(OH)D, when the baseline 25(OH)D was 54.3 nmol/L. The prevalence of serum 25(OH)D below < 50 nmol/L was halved. The changes were found for both sexes and were more pronounced in winter compared to summer months. Regular VitD supplementation had a significant positive effect on 25(OH)D at the age of 46, as well as had the dietary intake of fortified dairy products and fish, and the previous 25(OH)D concentration. However, the intake of fat-spreads albeit VitD-fortified, did not predict 25(OH)D.
Conclusion
Our results demonstrated the positive impact of the fortification programme on VitD status in middle-aged population.
Infertility and fecundability problems have been linked with lower 25-hydroxyvitamin D (25(OH)D) concentrations, but studies conducted with small, heterogenous or selected populations have shown ...inconsistent results.
This study included women at age 31 from prospective population-based Northern Finland Birth Cohort 1966. Serum 25(OH)D concentrations were evaluated between women with or without previous infertility examinations or treatments (infertility group,
= 375, reference group,
= 2051) and time to pregnancy (TTP) of over 12 months (decreased fecundability group,
= 338) with a wide range of confounders. Furthermore, 25(OH)D concentrations were also compared among reproductive outcomes.
The mean 25(OH)D concentration was lower and 25(OH)D < 30 nmol/L was more frequent in women with a history of infertility compared to reference group. Moreover, 25(OH)D > 75 nmol/L was more frequent in the reference group. The mean 25(OH)D concentration was lower in women who had had multiple miscarriages. Both history of infertility (β = -2.7, 95% confidence interval (CI) -4.6, -0.7) and decreased fecundability associated with lower 25(OH)D concentration (β = -4.1, 95% CI -7.4, -0.8) after adjustments. In conclusion, this population-based study demonstrated that previous infertility and decreased fecundability were associated with lower 25(OH)D.
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