Parental smoking during pregnancy and offspring bone mass at age 10?years: findings from a prospective birth cohort

Summary  

We investigated an intrauterine influence of maternal smoking during pregnancy on childhood bone mass. Daughters, but not sons, of mothers who smoked had higher bone mass at age 10 years. This appears to be due to familial factors related to parental smoking influencing increased offspring adiposity rather than a direct intrauterine effect.     

Itraconazole and inhaled fluticasone causing hypothalamic–pituitary–adrenal axis suppression in adults with cystic fibrosis

BackgroundAlthough there have been case reports of hypothalamic–pituitary–adrenal (HPA) axis suppression in patients with cystic fibrosis (CF) caused by the combination of oral itraconazole and inhaled fluticasone, to date no study has assessed the incidence of this potentially serious side effect.MethodsSynacthen tests were conducted on all patients with CF receiving itraconazole and inhaled fluticasone and an equal number of patients with CF receiving inhaled fluticasone but not itraconazole. Itraconazole levels were measured in patients receiving the therapy.ResultsTwelve patients receiving itraconazole and fluticasone underwent synacthen tests. All 12 had abnormal synacthen test results and 10/12 (83%) had HPA axis suppression. Two patients had severe HPA axis suppression with a peak cortisol < 75 nmol/L and further 3 patients had moderately severe suppression with a peak cortisol < 250 nmol/L. In contrast, only 2/12 on fluticasone alone had HPA axis suppression (both mild). The median (range) basal cortisol levels were significantly lower in those patients receiving itraconazole and inhaled fluticasone compared to those on fluticasone alone (219(22–508) nmol/L v 348(41–738) nnmol/L, p = 0.02), similar results were seen for peak cortisol levels (404(59–706) nmol/L v 672(432–1178) nmol/L, p < 0.001) and cortisol rise (179(37–240) nmol/L v 368(210–539) nmol/L, p < 0.001). The median (range) itraconazole level was 5.5(1.7–14.7) mg/L. Neither itraconazole levels nor fluticasone dose correlated with the degree of adrenal suppression.ConclusionsIn this study, all patients receiving itraconazole and inhaled fluticasone had abnormal synacthen test results. The incidence of HPA axis suppression with this treatment combination appears to be higher than that previously reported with itraconazole and inhaled budesonide.     

Longitudinal assessment of renal size and function in extremely low birth weight children at 7 and 11 years of age

Background

There are a lack of studies describing a longitudinal association between preterm delivery and renal complications later in life. We assessed renal size and function in preterm infants born with extremely low birth weight (ELBW) during 4 years of follow-up, comparing these parameters to age-matched children born full term (term controls).

Methods

The results of selected renal laboratory tests [levels of cystatin C, creatinine, blood urea nitrogen (BUN)] and of renal ultrasound evaluations were compared between the ELBW group and the term control group at age 7 and 11 years.

Results

The study population consisted of 64 children born with ELBW (ELBW children) who had been recruited at birth and 36 children born at term (term children) who took part in both follow-up assessments. Renal ultrasound examination revealed a significantly smaller renal volume in the 7- and 11-year-old ELBW children compared to the term controls [right kidney volume: 50.8 vs. 61.2 ml/m², respectively, at 7 years (p <0.01) and 51.4 vs. 58.2 ml/m², respectively, at 11 years (p <0.01); left kidney volume: 51.4 vs. 60.3 ml/m², respectively, at 7 years (p <0.01) and 55.2 vs. 60.7 ml/m², respectively, at 11 years (p?=?0.02)]. Renal function in ELBW children was also affected. Serum cystatin C levels were significantly higher in ELBW children than in the controls at 7 years of age, and this difference remained statistically significant at 11 years of age [0.63 vs. 0.59 mg/l, respectively, at 7 years (p?=?0.02) and 0.72 vs. 0.61 mg/l, respectively, at 11 years (p?=?0.01)]. Six ELBW children also had elevated cystatin C levels (0.97–1.11 mg/l) at 11 years of age. Cystatin C levels were within normal range in the ELBW children at age 7 years and in term children in both follow-up studies. BUN levels were higher in ELBW children at the age of 11 years (4.49 vs. 4.15 mmol/l; p?=?0.028).

Conclusion

Continued follow-up of these patients will reveal whether the observed worsening in renal function will persist into adulthood.

     

Longitudinal changes in lean mass predict pQCT measures of tibial geometry and mineralisation at 6–7 years

BackgroundStudies in childhood suggest that both body composition and early postnatal growth are associated with bone mineral density (BMD). However, little is known of the relationships between longitudinal changes in fat (FM) and lean mass (LM) and bone development in pre-pubertal children. We therefore investigated these associations in a population-based mother-offspring cohort, the Southampton Women's Survey.MethodsTotal FM and LM were assessed at birth and 6–7 years of age by dual-energy x-ray absorptiometry (DXA). At 6–7 years, total cross-sectional area (CSA) and trabecular volumetric BMD (vBMD) at the 4% site (metaphysis) of the tibia was assessed using peripheral quantitative computed tomography [pQCT (Stratec XCT-2000)]. Total CSA, cortical CSA, cortical vBMD and strength–strain index (SSI) were measured at the 38% site (diaphysis). FM, LM and bone parameters were adjusted for age and sex and standardised to create within-cohort z-scores. Change in LM (ΔLM) or FM (ΔFM) was represented by change in z-score from birth to 7 years old and conditioned on the birth measurement. Linear regression was used to explore the associations between ΔLM or ΔFM and standardised pQCT outcomes, before and after mutual adjustment and for linear growth. The β-coefficient represents SD change in outcome per unit SD change in predictor.ResultsDXA at birth, in addition to both DXA and pQCT scans at 6–7 years, were available for 200 children (48.5% male). ΔLM adjusted for ΔFM was positively associated with tibial total CSA at both the 4% (β = 0.57SD/SD, p < 0.001) and 38% sites (β = 0.53SD/SD, p < 0.001), cortical CSA (β = 0.48SD/SD, p < 0.001) and trabecular vBMD (β = 0.30SD/SD, p < 0.001), but not with cortical vBMD. These relationships persisted after adjustment for linear growth. In contrast, ΔFM adjusted for ΔLM was only associated with 38% total and cortical CSA, which became non-significant after adjustment for linear growth.ConclusionIn this study, gain in childhood LM was positively associated with bone size and trabecular vBMD at 6–7 years of age. In contrast, no relationships between change in FM and bone were observed, suggesting that muscle growth, rather than accrual of fat mass, may be a more important determinant of childhood bone development.     

Body size from birth to adulthood and bone mineral content and density at 31 years of age: results from the northern Finland 1966 birth cohort study

The purpose of this study was to evaluate the association between body size from birth to adulthood and bone mineral content (BMC) and bone mineral density (BMD) at the age of 31 years in a longitudinal study of the Northern Finland birth cohort for 1966. Data were collected at birth, 1, 14, and 31 years. This analysis was restricted to a subsample of individuals ( n =1,099) for whom the BMC (g) and BMD measurements (g/cm²) were performed on the distal and ultradistal radius by dual-energy X-ray absorptiometry (DXA) at the age of 31 years. Determinants of low BMC and BMD were analyzed using multivariate logistic regression. Growth retardation at birth, being underweight (BMI 20.0 kg/m²) at 31 years, and having a low calcium intake at 31 years were associated independently with low BMD at 31 years. Additionally, the proportion of subjects with low BMD was higher among those who had low standardized body weight (<1 SD) both at birth and at 14 years, and both at 14 and 31 years. Body weight at 31 years was the strongest associating factor of BCM at 31 years. Growth retardation at birth has long-lasting effects on adult bone mineral content and density of the distal and ultradistal radius independently of later body size, although adult body weight seems to be a most important determinant of BMC at the age of 31 years. Thinness and a low calcium intake are associated with low bone mineral content and density at 31 years of age. Further studies are needed to evaluate if these groups are at increased risk of osteoporosis in old age.     

Looking beyond hypogonadism: association between low testosterone and metabolic syndrome in men 20–59 years

International Urology and Nephrology - Rates of low testosterone and metabolic syndrome are increasing among adult men in the United States. Both are associated with increased cardiovascular...     

Renal function and systolic blood pressure in very-low-birth-weight infants 1–3?years of age

Background

Preterm very-low-birth-weight (PT-VLBW) infants are at risk of an elevated systolic blood pressure (SBP) in infancy and adulthood; however, the pathogenesis remains unclear. Altered renal development or function may be associated with increased SBP, but their contribution in PT-VLBW is unknown.

Methods

We determined renal function and its relationship to SBP in three groups of PT-VLBW at 1, 2, and 3?years of age, using serum cystatin-C to calculate the estimated glomerular filtration rate (eGFR).

Results

Cystatin-C levels decreased from 0.84?±?0.2 (SD) within the 1-year group to 0.70?±?0.1?mg/l (±SD; P?<?0.001) at 3?years and were unrelated to gender, fetal growth, and neonatal indomethacin exposure. eGFR rose from 121?±?59 in the 1-year group to 138?±?21?ml/min·1.73?m² (P?<?0.001) at 3?years. At 1?year, cystatin-C levels decreased with increasing SBP (P?<?0.007), and infants with SBP ≥?90th% had lower cystatin-C and higher eGFR (P?<?0.05). At 3?years, infants with lower birth weight (P?<?0.03) and gestational age (P?=?0.06) had reduced eGFR.

Conclusions

Preterm very-low-birth-weight infants demonstrate increasing renal function with advancing age. An elevated SBP and eGFR at 1?year suggests dysfunctional renal autoregulation and hyperfiltration, which may alter subsequent renal function and contribute to the lower eGFR seen at 3?years in infants with the lowest birth weight and gestational age.     

Trends in trabecular architecture and bone mineral density distribution in 152 individuals aged 30–90 years

The strength of trabecular bone depends on its microarchitecture and its tissue level properties. However, the interrelation between these two determinants of bone quality and their relation to age remain to be clarified. Iliac crest bone cores (n = 152) from individuals aged 30–90 years were analyzed by quantitative backscattered electron imaging. Univariate and multivariate analyses were conducted to determine whether epidemiological parameters (age, sex or BMI), structural histomorphometrical variables (BV/TV, Tb.Th, Tb.N and Tb.Sp) and osteoid-related indices (OV/BV, OS/BS or O.Th) predict the degree of bone mineralization. While sex and BMI were not associated with bone mineralization, age was positively correlated with the most frequently occurring calcium concentrations (Ca peak), the percentage of highly mineralized bone areas (Ca high) and, in the case of adjusted covariates, also the mean calcium content (Ca mean). Bone volume fraction and trabecular thickness were both negatively correlated with Ca mean. However, trabecular thickness was additionally associated with Ca peak, Ca high as well as the amount of low mineralized bone (Ca low) and was the only structural parameter predicting bone mineralization independent of age. Furthermore, our analyses demonstrated that osteoid variables – within a normal range (< 2% OV/BV) – were significantly associated with all mineralization parameters and represent the only predictor for the mineralization heterogeneity (Ca width). Taken together, we showed that elevated trabecular bone mineralization correlates with aging and bone loss. However, these associations are attributable to trabecular thinning that comes along with high bone mineralization due to the loss of low mineralized bone surfaces. Therefore, we demonstrated that the degree of areally resolved bone mineral is primarily associated with the amount of physiological osteoid present and the thickness of mineralized bone in trabeculae.     

Risperidone induced reproductive toxicity in male rats targeting leydig cells and hypothalamic–pituitary–gonadal axis by inducing oxidative stress

Risperidone (RIS), a commonly used drug during a lifetime for the treatment of schizophrenia, causes some adverse effects in the male reproductive system; however, there is no comprehensive reproductive toxicity study of RIS. For this purpose, male rats were administered orally for 1.25, 2.5 and 3 mg/kg RIS for 28 days and the sperm count, motility, morphology, DNA damage and the histological changes in testicular tissue were evaluated. Follicle-stimulating hormone (FSH), luteinising hormone (LH) and serum levels of testosterone, which are the main hormonal regulators of reproduction, and testicular glutathione (GSH), catalase (CAT), superoxide dismutase (SOD) and malondialdehyde (MDA) levels as the indicators of oxidative stress were determined. Normal sperm morphology was decreased in RIS groups and histopathological degeneration occurred in testis tissue dose-dependently. Serum LH levels were not altered; however, FSH and testosterone levels decreased in the high-dose group. Histopathologic examination showed RIS toxicity targeted Leydig cells, which might be associated with impairment of the hypothalamic–pituitary–gonadal (HPG) axis. GSH levels were decreased and MDA levels were increased in the high-dose group which was evaluated as indicators of oxidative stress. In conclusion, RIS caused reproductive toxicity in male rats by inducing oxidative stress and disrupting hormonal regulation.     

Detection of bone and cartilage-related proteins in plasma of patients with a bone fracture using liquid chromatography–mass spectrometry

Following bone fracture, a large number of growth factors, cytokines, and their cognate receptors involved in the repair process are active at the fracture site. To determine whether they appear in patients’ blood as candidate biomarkers for following the outcome of healing, we analysed the plasma of 25 patients with an acute bone fracture following affinity plasma purification, SDS gel electrophoresis and liquid chromatography - tandem mass spectrometry (LC-MS/MS). Two hundred and thirteen nonredundant proteins were identified in the in-gel analysis of pooled plasma proteins. Gene ontology (GO) analysis indicated that a majority of detected proteins were of extracellular origin, whereas only a small number were of intracellular (cytosol and nucleus) origin. A significant proportion of detected proteins was involved in the cell growth and proliferation, transport and coagulation. Twelve proteins were potentially related to bone and cartilage metabolism, and several have not been previously identified in the plasma, including: TGF-β induced protein IG-H₃, cartilage acidic protein 1, procollagen C proteinase enhancer protein and TGF-β receptor III.

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Résumé Après une fracture, un grand nombre de facteurs de croissance, cytokines et leurs récepteurs apparentés interviennent dans le processus de réparation des foyers de fracture. Nous avons analysé ces différents facteurs circulants chez 25 patients ayant présenté une fracture après purification du sang, électrophorèses, chromatographie et spectrographie de masse. 213 protéines ont été identifiées. L’analyse génétique de la majorité de ces protéines montre qu’elles sont d’origine extra cellulaires avec un très petit nombre de protéines intra cellulaires provenant notamment du noyau. Une proportion significative des protéines détectées intervient au niveau de la croissance, de la prolifération cellulaire et des phénomènes de coagulation. 12 protéines sont spécifiquement en rapport avec les métabolismes osseux et cartilagineux, plusieurs d’entre-elles n’avaient pas été préalablement identifiées au niveau du plasma comme la TGF-β, la protéine IG-H3, la CAP 1, le procollagène de type C, le TGF-β récepteur III.

     

Tracking of size-adjusted bone mineral content and bone area in boys and girls from 10 to 17 years of age

Summary  

Positive correlations for bone mineral content (BMC) between 10 and 17 years of age were found for boys and girls after adjusting for body size, puberty, and diet. This tracking of BMC indicated that osteoporosis prevention should begin already in prepuberty.     

Faecal incontinence 20 years after one birth: a comparison between vaginal delivery and caesarean section

Introduction and hypothesis

The aetiology of bowel incontinence in middle-aged women is multifactorial and the contribution of birth-related factors later in life is still poorly defined. The aim was to assess prevalence, risk factors and severity of faecal (FI, defined as the involuntary loss of faeces—solid or liquid) and anal incontinence (AI, includes FI as well as the involuntary loss of flatus) 20 years after one vaginal (VD) or one caesarean section (CS).

Methods

This was a registry-based national cohort study of primiparae giving birth in 1985–1988 and having no further births (n?=?5,236). Data from the Swedish Medical Birth Register were linked to information from a pelvic floor disorder questionnaire in 2008 (response rate 65.2 %). Analysis of variance and multivariate analysis were used to obtain adjusted prevalence and odds ratios (adj-OR).

Results

Overall prevalences of FI and AI were 13.6 and 47.0 %. FI prevalence was higher after VD compared with CS [14.5 versus 10.6 %, adj-OR 1.43, 95 % confidence interval (CI) 1.16–1.77] but was not increased after acute versus elective CS. Perineal tear (≥second degree) increased the prevalence and risk of FI compared with no tear (22.8 versus 13.9 %, adj-OR 1.95, 95 % CI 1.33–2.85). The prevalence of FI was lower after VD with an episiotomy (11.1 %) and similar to that after CS (10.6 %). With each unit increase of current body mass index the odds of FI increased by 6 % (OR 1.06, 95 % CI 1.04–1.08).

Conclusions

Late FI and AI prevalences were higher after VD compared with CS. Perineal tear (≥second degree) versus no tear doubled the prevalence of FI. FI prevalence was similar after a CS and a VD combined with episiotomy.     

Synovium CD20 expression is a potential new predictor of bone erosion progression in very-early arthritis treated by sequential DMARDs monotherapy – A pilot study from the VErA cohort

ObjectiveBecause available biomarkers (rheumatoid factors [RF], anti-cyclic citrullinated autoantibodies [anti-CCP2], erythrocyte sedimentation rate at 1st hour [ESR]/C-reactive peptide [CRP] and bone erosions) are insufficient to predict rheumatoid arthritis (RA) structural damage, to determine whether synovium expression of greater or equal to 1 markers could constitute new prognostic factor(s).MethodThe study was conducted on 18 prospectively enrolled disease-modifying anti-rheumatic drug (DMARD)- and glucocorticoid-naïve, VErA cohort patients with very-early arthritis (median duration: 4 months). Recorded at baseline were: clinical and biological (serum ESR, CRP, RF-isotypes, anti-CCP2, osteoprotegerin, receptor activator of nuclear κB-ligand [RANK-L] and cartilage oligomeric matrix protein [COMP] levels) data; synovium expression (HLA-DR, CD163, CD3, CD20, VEGF, osteoprotegerin, RANK-L, Bcl2 and global inflammation index) for a metacarpophalangeal joint-synovium biopsy. Baseline and 3-year hand-and-foot X-rays were graded with the van der Heijde-modified-Sharp score; the judgment criterion was its progression during follow-up. Pearson's product moment correlation statistics were used to test for association between paired samples.ResultsA baseline, a significant relationship was found between erosive damage and markers of B-cell activation, notably the synovium CD20 expression (r = 0.68; P = 0.0001). Quantified by the modified-Sharp erosion score variation, the 3-year structural damage progression was significantly correlated with: serum levels of RF-IgG (r = 0.75; P = 0.0003), -IgM (r = 0.69; P = 0.001), anti-CCP2 (r = 0.53; P = 0.02) and RANK-L (r = 0.61; P = 0.007); synovium CD20 expression (r = 0.70; P = 0.001).ConclusionThis analysis of the prognostic value of a large panel of synovium markers in a limited sample of prospectively followed, well-documented patients suggested that both synovial CD20 and serum RANK-L levels might be new predictors of structural damage progression in very-early RA.     

Fracture patterns and bone mass in South African adolescent–mother pairs: the Birth to Twenty cohort

Summary

The associations of fracture prevalence and bone mass in adolescents with maternal fracture history and bone mass have not been investigated previously in South Africa. Maternal bone mass has a significant inverse association with their adolescents' fracture rates and bone mass across all ethnic groups.

Introduction

Differences in fracture rates and bone mass between families and individuals of different ethnic origins may be due to differing lifestyles and/or genetic backgrounds. This study aimed to assess associations of fracture prevalence and bone mass in adolescents with maternal fracture history and bone mass, and sibling fracture history.

Methods

Data from 1,389 adolescent–biological mother pairs from the Birth to Twenty longitudinal study were obtained. Questionnaires were completed on adolescent fractures until 17/18 years of age and on sibling fractures. Biological mothers completed questionnaires on their own fractures prior to the age of 18 years. Anthropometric and bone mass data on adolescent–biological mother pairs were collected.

Results

An adolescent's risk of lifetime fracture decreased with increasing maternal lumbar spine (LS) bone mineral content (BMC; 24 % reduction in fracture risk for every unit increase in maternal LS BMC Z-score) and increased if they were white, male, or had a sibling with a history of fracture. Adolescent height, weight, male gender, maternal bone area and BMC, and white ethnicity were positive predictors of adolescent bone mass. White adolescents and their mothers had a higher fracture prevalence (adolescents 42 %, mothers 31 %) compared to the black (adolescents 20 %, mothers 6 %) and mixed ancestry (adolescents 20 %, mothers 16 %) groups.

Conclusion

Maternal bone mass has a significant inverse association with their adolescent off-springs' fracture risk and bone mass. Furthermore, there is a strong familial component in fracture patterns among South African adolescents and their siblings.     

Pelvis width associated with bone mass distribution at the proximal femur in children 10–11 years old

Differences in skeletal geometry may generate different patterns of mechanical loading to bone. Impact and muscle loading during physical activity have been shown to influence skeletal geometry. The purpose of this study was to compare geometric measures of the pelvis and proximal femur (PF) of young children and to analyze the contribution and potential interaction of these geometric measures with physical activity on PF bone mass distribution. Participants were 149 girls and 145 boys, aged 10–11 years. Total body and left hip DXA scans were used to derive pelvic and PF geometric measures and PF bone mineral density (BMD) at the femoral neck (FN), trochanter (TR), and intertrochanter (IT). These subregions were used to represent bone mass distribution via three BMD ratios: FN:PF, TR:PF, and IT:PF. Physical activity was objectively measured using accelerometry, and maturity was estimated as the years of distance from peak height velocity. When compared to boys, girls had a wider pelvic diameter and greater interacetabular distances (p < 0.001), lower BMD at FN, TR, and IT (p < 0.05), and higher TR:PF (p < 0.001). After controlling for maturity, body height, and lean body mass, the interacetabular distance in girls explained 21.1 % (β = 0.713, p < 0.001) in TR:PF and 2.9 % (β = ?0.179, p = 0.031) in the IT:PF. Neck–shaft angle explained 5.6 % (β = ?0.265, p = 0.001) of the IT:PF and 3.1 % (β = 0.194, p = 0.018) of the FN:PF. In boys, FN axis length explained 2.9 % (β = 0.195, p = 0.040) of TR:PF. There was no main effect of physical activity or interaction effect with pelvic geometry in explaining BMD differences among the subregions of the PF. Even before sexual dimorphism, girls have a wider pelvis than boys, which accounted for proportionally greater BMD of the TR than other subregions of the PF.