Maria de Ridder

Reference data for bone density and body composition measured with dual energy x ray absorptiometry in white children and young adults

Aims: To obtain normative data on bone mineral density and body composition measured with dual energy x ray absorptiometry (DXA) from early childhood to young adulthood. Methods: Cross sectional results from 444 healthy white volunteers (4–20 years) in the Netherlands were combined with the results from 198 children who agreed to participate in the follow up study approximately four years later. DXA (Lunar, DPXL) of lumbar spine and total body was performed to assess bone density and body composition. Results: Bone density and lean body mass (LBM) increased with age. Maximal increase in bone density and LBM occurred around the age of 13 years in girls and approximately two years later in boys. Bone density of total body and lumbar spine showed an ongoing slight increase in the third decade. Mean fat percentage in boys remained at 10.5% throughout childhood, but increased in girls. Conclusions: Most of the skeletal mass in lumbar spine and total body is reached before the end of the second decade, with a slight increase thereafter. This study provides reference values for bone density and body composition measured with DXA for children and young adults.

The Association Between Blood Pressure, Hypertension, and Cerebral White Matter Lesions Cardiovascular Determinants of Dementia Study

Cerebral white matter lesions are frequently observed on magnetic resonance imaging (MRI) scans in elderly people and are associated with stroke and dementia. Elevated blood pressure is presumed one of the main risk factors, although data are almost exclusively derived from cross-sectional studies. We assessed in 10 European cohorts the relation between concurrently and previously measured blood pressure levels, hypertension, its treatment, and severe cerebral white matter lesions. In total, 1805 nondemented subjects aged 65 to 75 years were sampled from ongoing community-based studies that were initiated 5 to 20 years before the MRI. White matter lesions in the periventricular and subcortical region were rated separately using semiquantitative measures. We performed logistic regression analyses adjusted for potential confounders in 1625 people with complete data. Concurrently and formerly assessed diastolic and systolic blood pressure levels were positively associated with severe white matter lesions. Both increases and decreases in diastolic blood pressure were associated with more severe periventricular white matter lesions. Increase in systolic blood pressure levels was associated with more severe periventricular and subcortical white matter lesions. People with poorly controlled hypertension had a higher risk of severe white matter lesions than those without hypertension, or those with controlled or untreated hypertension. Higher blood pressure was associated with an increased risk of severe white matter lesions. Successful treatment of hypertension may reduce this risk; however, a potential negative effect of decreasing diastolic blood pressure level on the occurrence of severe periventricular white matter lesions should be taken into account.

Effects of Environmental Exposure to Polychlorinated Biphenyls and Dioxins on Birth Size and Growth in Dutch Children

Lower birth weight and growth retardation has been found in studies with laboratory animals, in children born of mothers exposed to accidental high levels of polychlorinated biphenyls (PCBs) and related compounds, and in children born of mothers who consumed PCB-contaminated fish. The effect of background exposure to PCBs and dioxins on birth size and growth in human newborns, however, is still unknown. This study examined birth size and postnatal growth of term newborns in relation to their background PCB and dioxin exposure. Birth weight and weight, length, and head circumference were measured at 10 d and 3, 7, 18, and 42 mo of age in 207 children, of whom 105 were breast-fed and 102 were formula-fed during infancy. The effect of in utero exposure to PCBs on birth size, assessed by cord and maternal plasma PCB levels, was investigated in the whole group. The effect of prenatal PCB exposure on postnatal growth was studied in the formula-fed group, whereas the effect of prenatal as well as lactational exposure to PCBs and dioxins on postnatal growth was studied in the breast-fed group. After adjustment for covariates, cord and maternal plasma PCB levels where both negatively associated with birth weight. Infants with high cord plasma PCB levels (P90 = 0.80 µg/L) weighed 165 g less compared with infants with low cord plasma PCB levels (P10 = 0.20 µg/L). Cord and maternal plasma PCB levels where both significantly associated with lower growth rate, defined as change in SD score (SDS) of weight, length, and head circumference from birth to 3 mo in the formula-fed group (all p values <0.05). No negative effects of prenatal PCB exposure on growth rate were found from 3 to 42 months of age. Postnatal PCB and dioxin exposure was not negatively associated with growth rate in the breast-fed group. In utero exposure to environmental levels of PCBs is negatively associated with birth weight and postnatal growth until 3 mo of age. Although this growth delay was described in healthy term born infants, intrauterine and postnatal growth retardation are potentially harmful to the developing human and should be avoided by reducing maternal PCB and dioxin body burden, and consequently fetal exposure to these pollutants.

Immunologic Effects of Background Prenatal and Postnatal Exposure to Dioxins and Polychlorinated Biphenyls in Dutch Infants

ABSTRACT: Immunologic effects of pre- and postnatal polychlorinated biphenyl (PCB)/dioxin exposure in Dutch infants from birth to 18 mo of age are explored. The total study group consisted of 207 healthy mother-infant pairs, of which 105 infants were breast-fed and 102 children were bottle-fed. Prenatal PCB exposure was estimated by the PCB sum (PCB congeners 118, 138, 153, and 180) in maternal blood and the total toxic equivalent (TEQ) level in human milk (17 dioxin and 8 dioxin-like PCB congeners). Postnatal PCB/dioxin exposure was calculated as a product of the total TEQ level in human milk multiplied by the weeks of breast-feeding. The number of periods with rhinitis, bronchitis, tonsillitis, and otitis during the first 18 mo of life was used as an estimate of the health status of the infants. Humoral immunity was measured at 18 mo of age by detecting antibody levels to mumps, measles, and rubella. White blood cell counts (monocytes, granulocytes, and lymphocytes) and immunologic marker analyses CD4+ T-lymphocytes, CD8+ T-lymphocytes, activated T-lymphocytes (HLA-DR+CD3+), as well as T cell receptor (TcR) αβ+, TcRγδ+, CD4+CD45RA+ and CD4+CD45RO+ T-lymphocytes, B-lymphocytes (CD19+ and/or CD20+) and NK cells (CD16+ and/or CD56+/CD3−) in cord blood and venous blood at 3 and 18 mo of age were assessed in a subgroup of 55 infants. There was no relationship between pre-and postnatal PCB/dioxin exposure and upper or lower respiratory tract symptoms or humoral antibody production. A higher prenatal PCB/ dioxin exposure was associated with an increase in the number of TcRγδ+ T cells at birth and with an increase in the total number of T cells and the number of CD8+ (cytotoxic), TcRαβ+, and TcRγδ+ T cells at 18 mo of age. A higher prenatal as well as postnatal PCB/dioxin exposure was associated with lower monocyte and granulocyte counts at 3 mo of age. In conclusion, our study suggests that background levels of PCB/dioxin exposure influences the human fetal and neonatal immune system.

Adrenal function in sick very preterm infants

Some very preterm neonates admitted to the neonatal intensive care unit show circulatory and respiratory problems that improve after administration of steroids. It is unclear whether these symptoms could be caused by adrenal insufficiency. The objective of our study was to investigate the cortisol levels and the cortisol release from the adrenals after ACTH in very preterm infants with and without severe illness and to find whether a relation exists between adrenal function and outcome. An ACTH test (0.5 μg) was performed on d 4 in 21 very preterm infants (gestational age, 25.6–29.6 wk; birth weight, 485–1265 g). Baseline cortisol and 17-hydroxyprogesterone (17OHP) levels and the cortisol levels 30, 60, and 120 min after ACTH administration were measured. The Score for Neonatal Acute Physiology was used to measure illness severity. All infants showed an increase in cortisol levels after ACTH, but the cortisol levels were significantly lower in the ventilated more severely ill infants. After adjusting for birth weight and gestational age, the mean baseline cortisol levels and cortisol/17OHP ratios were significantly lower and the 17OHP levels significantly higher in the ventilated infants compared with the nonventilated infants. Patients with an adverse outcome had significantly lower baseline cortisol/17OHP ratios and 60-min cortisol levels during ACTH testing (p = 0.002 and p = 0.03, respectively). These data suggest an insufficient adrenal response to stress in sick ventilated very preterm infants with gestational ages younger than 30 wk compared with nonventilated less sick preterm infants. Further studies are required to investigate whether supplementation with physiologic doses of hydrocortisone may benefit the outcome.

Peak bone mineral density, lean body mass and fractures

BACKGROUND During childhood and adolescence, bone mass and lean body mass (LBM) increase till a plateau is reached. In this longitudinal and cross-sectional study, the age of reaching the plateau was evaluated for lumbar spine and total body bone mass measurements and lean body mass. The association between fractures and bone mineral density (BMD) was studied. PATIENTS AND METHODS We included 501 healthy participants, 141 males and 360 females, aged 13-29 years. Of these 90 had participated in a previous longitudinal study of 444 participants, aged 4-20 years (for the first measurement) and 198 participants, aged 8-25 years (for a second measurement). BMD and body composition were measured with dual energy X-ray absorptiometry (DXA). Volumetric BMD (bone mineral apparent density, BMAD) was calculated. All the data were used to determine the age of reaching the plateau. RESULTS The plateau for lumbar spine BMD, BMAD, total body BMD, bone mineral content and LBM was reached between 18 and 20 years of age in females and between 18 and 23 years in males. The prevalence of fractures was 37% in males and 28% in females. Total body BMD Z-score was significantly lower in all participants who had had a fracture (p<0.05), whereas lumbar spine BMD and BMAD was only significantly lower in females who had had fractures (p=0.007 and p<0.001, respectively). Mean lumbar spine BMAD Z-score at the previous measurement was significantly lower in the participants who had a first fracture between the last two measurements (p=0.04). CONCLUSION Peak BMD and peak LBM were attained between 18 and 20 years in females and between 18 and 23 years in males in this study using longitudinal and cross sectional data in the age range of 4 to 30 years. A significantly lower total body BMD was seen in participants who had had a fracture and a lower lumbar spine BMD and BMAD in females who had had a fracture. Lumbar spine BMAD Z-score seems to be a good predictor for future fractures.

Cerebral changes on MRI and cognitive function: the CASCADE study.

The aging, non-demented brain undergoes several physiological changes, some of which may affect cognitive function. The goal of the present study was to examine the associations between subcortical and periventricular white matter hyperintensities (WMHs), cortical and subcortical atrophy, and cognitive function (episodic memory, word fluency, attention, and perceptual, cognitive, and motor speed). This was done within a European collaborative study, Cardiovascular Determinants of Dementia (CASCADE), in which magnetic resonance imaging (MRI) was performed on community-dwelling individuals. The study includes 1254 persons from eight European study centers, ranging between 64 and 76 years of age (M 69.4+/-3.3; 55% men). When demographics (age, education, and sex), study center, and concurrent brain changes had been adjusted for, periventricular WMHS predicted lower performance in word fluency and the Stroop test (time), and subcortical atrophy predicted lower performance in motor speed and the Stroop test (errors). The findings are consistent with findings from lesion and functional neuroimaging studies.

Efficacy and safety of oxandrolone in growth hormone-treated girls with turner syndrome.

CONTEXT AND OBJECTIVE GH therapy increases growth and adult height in Turner syndrome (TS). The benefit to risk ratio of adding the weak androgen oxandrolone (Ox) to GH is unclear. DESIGN AND PARTICIPANTS A randomized, placebo-controlled, double-blind, dose-response study was performed in 10 centers in The Netherlands. One hundred thirty-three patients with TS were included in age group 1 (2-7.99 yr), 2 (8-11.99 yr), or 3 (12-15.99 yr). Patients were treated with GH (1.33 mg/m(2) . d) from baseline, combined with placebo (Pl) or Ox in low (0.03 mg/kg . d) or conventional (0.06 mg/kg . d) dose from the age of 8 yr and estrogens from the age of 12 yr. Adult height gain (adult height minus predicted adult height) and safety parameters were systematically assessed. RESULTS Compared with GH+Pl, GH+Ox 0.03 increased adult height gain in the intention-to-treat analysis (mean +/- sd, 9.5 +/- 4.7 vs. 7.2 +/- 4.0 cm, P = 0.02) and per-protocol analysis (9.8 +/- 4.9 vs. 6.8 +/- 4.4 cm, P = 0.02). Partly due to accelerated bone maturation (P < 0.001), adult height gain on GH+Ox 0.06 was not significantly different from that on GH+Pl (8.3 +/- 4.7 vs. 7.2 +/- 4.0 cm, P = 0.3). Breast development was slower on GH+Ox (GH+Ox 0.03, P = 0.02; GH+Ox 0.06, P = 0.05), and more girls reported virilization on GH+Ox 0.06 than on GH+Pl (P < 0.001). CONCLUSIONS In GH-treated girls with TS, we discourage the use of the conventional Ox dosage (0.06 mg/kg . d) because of its low benefit to risk ratio. The addition of Ox 0.03 mg/kg . d modestly increases adult height gain and has a fairly good safety profile, except for some deceleration of breast development.

Risk of Upper Gastrointestinal Bleeding From Different Drug Combinations

BACKGROUND & AIMS Concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) and low-dose aspirin increases the risk of upper gastrointestinal bleeding (UGIB). Guidelines suggest avoiding certain drug combinations, yet little is known about the magnitude of their interactions. We estimated the risk of UGIB during concomitant use of nonselective (ns)NSAIDs, cyclooxygenase -2 selective inhibitors (COX-2 inhibitors), and low-dose aspirin with other drugs. METHODS We performed a case series analysis of data from 114,835 patients with UGIB (930,888 person-years of follow-up) identified from 7 population-based health care databases (approximately 20 million subjects). Each patient served as his or her own control. Drug exposure was determined based on prescriptions of nsNSAIDs, COX-2 inhibitors, or low-dose aspirin, alone and in combination with other drugs that affect the risk of UGIB. We measured relative risk (incidence rate ratio [IRR] during drug exposure vs nonexposure) and excess risk due to concomitant drug exposure (relative excess risk due to interaction [RERI]). RESULTS Monotherapy with nsNSAIDs increased the risk of diagnosis of UGIB (IRR, 4.3) to a greater extent than monotherapy with COX-2 inhibitors (IRR, 2.9) or low-dose aspirin (IRR, 3.1). Combination therapy generally increased the risk of UGIB; concomitant nsNSAID and corticosteroid therapies increased the IRR to the greatest extent (12.8) and also produced the greatest excess risk (RERI, 5.5). Concomitant use of nsNSAIDs and aldosterone antagonists produced an IRR for UGIB of 11.0 (RERI, 4.5). Excess risk from concomitant use of nsNSAIDs with selective serotonin reuptake inhibitors (SSRIs) was 1.6, whereas that from use of COX-2 inhibitors with SSRIs was 1.9 and that for use of low-dose aspirin with SSRIs was 0.5. Excess risk of concomitant use of nsNSAIDs with anticoagulants was 2.4, of COX-2 inhibitors with anticoagulants was 0.1, and of low-dose aspirin with anticoagulants was 1.9. CONCLUSIONS Based on a case series analysis, concomitant use of nsNSAIDs, COX-2 inhibitors, or low-dose aspirin with SSRIs significantly increases the risk of UGIB. Concomitant use of nsNSAIDs or low-dose aspirin, but not COX-2 inhibitors, with corticosteroids, aldosterone antagonists, or anticoagulants produces significant excess risk of UGIB.

Fetal Venous and Arterial Flow Velocity Wave Forms between Eight and Twenty Weeks of Gestation

Our purpose was to study the nature and gestational age dependency of fetal venous Doppler flow velocity wave forms and their relationship with fetal arterial wave forms in early pregnancy. Venous and arterial Doppler recordings were performed in 262 normal singleton pregnancies according to a cross-sectional study design at 8-20 wk of gestation. A statistically significant age-dependent increase is established for the umbilical vein, ductus venosus, and inferior vena cava time-averaged velocity. Umbilical venous pulsatile flow patterns are observed up to 15 wk of gestation. The pulsatility index for veins in all three venous vessels displays a gestational age-dependent reduction. No relation can be established between the pulsatility index for veins and the pulsatility index in the descending aorta and umbilical artery. This may be explained by the fact that the pulsatility index for veins reflects cardiac ventricular preload, whereas the pulsatility index in the arterial vessels reflects down-stream impedance at fetal placental level.Our purpose was to study the nature and gestational age dependency of fetal venous Doppler flow velocity wave forms and their relationship with fetal arterial wave forms in early pregnancy. Venous and arterial Doppler recordings were performed in 262 normal singleton pregnancies according to a cross-sectional study design at 8-20 wk of gestation. A statistically significant age-dependent increase is established for the umbilical vein, ductus venosus, and inferior vena cava time-averaged velocity. Umbilical venous pulsatile flow patterns are observed up to 15 wk of gestation. The pulsatility index for veins in all three venous vessels displays a gestational age-dependent reduction. No relation can be established between the pulsatility index for veins and the pulsatility index in the descending aorta and umbilical artery. This may be explained by the fact that the pulsatility index for veins reflects cardiac ventricular preload, whereas the pulsatility index in the arterial vessels reflects downstream impedance at fetal placental level.