Differential relationships between parent-child DXA and pQCT bone measures: Results from the Southampton Women's Survey.

AIM: To investigate the associations between indices of bone health in childhood and corresponding parental measures. METHODS: The Southampton Women's Survey characterised 12,583 non-pregnant women aged 20-34 years; 3158 subsequently had singleton live births. In a subset, dual-energy X-ray absorptiometry (DXA) measurements of bone area (BA), bone mineral content (BMC) and areal bone mineral density (aBMD) lumbar spine and total hip were obtained in the parent/offspring (aged 8-9 years) trios. Another subset of children (aged 6-7 years), and their parents, had peripheral quantitative computed tomography (pQCT; 4% and 38% tibia) measures. Using multivariable linear regression we examined relationships between mother/father and offspring, adjusting for parental age, habitual walking speed and education; offspring age and sex; and the corresponding bone measure in the other parent (ß-coefficients (95%CI) unit/unit for each bone measure). RESULTS: Data were available for 260 trios with DXA and 99 with pQCT. There were positive associations for BA, BMC and aBMD between either parent and offspring. Mother-child associations were of greater magnitude than father-child; for example, mother-child aBMD (ß = 0.26 g·cm-2/g·cm-2 (0.21,0.32)) and father-child aBMD (ß = 0.16 g·cm-2/g·cm-2 (0.11,0.21)), P-difference in ß = 0.007. In the subset with pQCT there was a positive association for mother-offspring 4% tibial total area (ß = 0.33 mm2/mm2 (0.17,0.48)), but little evidence of a father-offspring association (ß = -0.06 mm2/mm2 (-0.17,0.06)). In contrast offspring 38% cortical density was more strongly associated with this measure in fathers (ß = 0.48 mg·cm-3/mg·cm-3 (0.15,0.82)) than mothers (ß = 0.27 mg·cm-3/mg·cm-3 (-0.03,0.56)). In general mother-father differences were attenuated by adjustment for height. CONCLUSIONS: Whilst offspring bone measures are independently associated with those of either parent, the magnitude of the association is often greater for maternal than paternal relationships. These findings are consistent with an in utero influence on offspring growth but might also reflect genetic and/or epigenetic parent of origin effects. SUMMARY: In an established parent-offspring cohort, associations between parent and offspring bone indices were generally greater in magnitude for mother-offspring than father-offspring relationships.

Validity of parental recall of children's fracture: implications for investigation of childhood osteoporosis.

UNLABELLED: Fracture history is an important component of osteoporosis diagnosis in children. One in six parentally reported lifetime fractures in children were not confirmed on review of radiographs. Care should be taken to avoid unnecessary investigations for possible osteoporosis due to parental over-reporting of soft tissue injuries as fractures. INTRODUCTION: The diagnosis of osteoporosis in children requires either a vertebral compression fracture, or a significant fracture history (defined as ≥2 long bone fractures <10 years or ≥3 long bone fractures <19 years, excluding high impact fractures) and low bone mineral density. As children with frequent fractures might benefit from further evaluation, we determined whether parental reports of lifetime fracture were accurate compared to radiological reports and if they appropriately selected children for further consideration of osteoporosis. METHODS: Parents of children (<18 years) with a musculoskeletal injury completed a questionnaire on their child's fracture history, including age, site and mechanism of previous fracture(s). Radiological reports were reviewed to confirm the fracture. RESULTS: Six hundred sixty parents completed the questionnaire and reported 276 previous fractures in 207 children. An injury treated at our hospital was recorded in 214 of the 276 parentally reported fractures. Thirty-four of 214 (16 %) were not a confirmed fracture. An injury was recorded for all parentally reported fractures in 150 children, but for 21 % children, there were inaccurate details (no evidence of fracture, incorrect site or forgotten fractures) on parent report. Eighteen of 150 children had a significant fracture history on parental report alone, but following review of radiology reports, 2 of 18 (11 %) did not have clinically significant fracture histories. CONCLUSIONS: Approximately one in six fractures reported by parents to have occurred in their child's lifetime had not resulted in a fracture. One in nine children with a significant fracture history could have been investigated unnecessarily.

Vitamin D and skeletal health in infancy and childhood.

During growth, severe vitamin D deficiency in childhood can result in symptomatic hypocalcaemia and rickets. Despite the suggestion from some studies of a secular increase in the incidence of rickets, this observation may be driven more by changes in population demographics than a true alteration to age, sex and ethnicity-specific incidence rates; indeed, rickets remains uncommon overall and is rarely seen in fair-skinned children. Additionally, the impact of less severe vitamin D deficiency and insufficiency has received much interest in recent years, and in this review, we consider the evidence relating vitamin D status to fracture risk and bone mineral density (BMD) in childhood and adolescence. We conclude that there is insufficient evidence to support the suggestion that low serum 25-hydroxyvitamin D [25(OH)D] increases childhood fracture risk. Overall, the relationship between 25(OH)D and BMD is inconsistent across studies and across skeletal sites within the same study; however, there is evidence to suggest that vitamin D supplementation in children with the lowest levels of 25(OH)D might improve BMD. High-quality randomised trials are now required to confirm this benefit.

Identifying targets to reduce the incidence of diabetic ketoacidosis at diagnosis of type 1 diabetes in the UK.

BACKGROUND: Diabetic ketoacidosis (DKA) is the leading cause of mortality in childhood diabetes, and at diagnosis might represent delayed presentation. The extent and reasons for delays are unclear, but identifying and targeting factors associated with DKA could reduce this incidence. OBJECTIVE: To compare the patient pathway before diagnosis of type 1 diabetes mellitus (T1DM) in children presenting with DKA and non-acidotic hyperglycaemia. DESIGN, SETTING AND PATIENTS: Over a 3-month period, children newly diagnosed with T1DM were identified on admission to UK hospitals. Parents and medical teams completed a questionnaire about events before diagnosis. RESULTS: Data were available for 261 children (54% male), median age 10.3y (range 0.8-16.6 y). 25% presented with DKA, but more commonly in children <2y (80% vs 23%, p<0.001). Fewer children with DKA reported polyuria (76% vs 86%) or polydipsia (86% vs 94%) (both p<0.05), but more reported fatigue (74% vs 52%) and weight loss (75% vs 54%) (both p<0.01). 24% of children had multiple healthcare professional (HCP) contacts, and these children had lower pH on admission. 46% of children with a delayed presentation to secondary care had non-urgent investigations. 64% of parents had considered a diagnosis of diabetes, and these children were less likely to present with DKA (13% vs 47%, p<0.001). CONCLUSIONS: Multiple HCP contacts increased risk of presentation in DKA, whereas, parental awareness of diabetes was protective. Improved public and health professional education targeting non-classical symptoms, awareness of diabetes in under 2 y, and point-of-care testing could reduce DKA at diagnosis of diabetes.

Children with nephrotic syndrome have greater bone area but similar volumetric bone mineral density to healthy controls.

BACKGROUND: Glucocorticoid use has been associated with an increased fracture risk and reduced bone mineral density (BMD), particularly in the trabecular compartment. However the contribution of the underlying inflammatory disease process to these outcomes is poorly understood. Childhood nephrotic syndrome (NS) typically follows a relapsing-remitting course often requiring recurrent courses of glucocorticoids, but with low systemic inflammation during remission. NS therefore represents a useful clinical model to investigate the effects of glucocorticoids on BMD and bone geometry in childhood. METHODS: Children with NS were compared to age and sex matched healthy controls. Body composition and areal BMD (whole body, lumbar spine and hip) were assessed by DXA. Peripheral quantitative computed tomography (pQCT) scans were obtained at metaphyseal (4%) and diaphyseal (66%) sites of the tibia to determine volumetric BMD and bone cross-sectional geometry. Lifetime cumulative glucocorticoid exposure was calculated from medical records. RESULTS: 29 children with NS (55% male, age 10.7±3.1years) were compared to 29 healthy controls (55% male, age 11.0±3.0years). The children with NS were of similar height SDS to controls (p=0.28), but were heavier (0.65±1.28SDS vs -0.04±0.89SDS, p=0.022) and had greater body fat percentage SDS (0.31±1.01 vs -0.52±1.10, p=0.008). Tibial trabecular and cortical vBMD were similar between the two groups but bone cross-sectional area (CSA) was significantly greater in children with NS at both the metaphysis (954±234mm(2) vs 817±197mm(2), p=0.002) and diaphysis (534.9±162.7mm(2) vs 463.2±155.5mm(2), p=0.014). Endosteal and periosteal circumferences were greater in children with NS than controls (both p<0.01), resulting in reduced cortical thickness (2.4±0.7mm vs 2.8±0.7mm, p=0.018), but similar cortical CSA (p=0.22). The differences in cortical geometry were not statistically significant when weight was included as a confounding factor. There were no associations between cumulative steroid exposure, duration of NS or number of relapses and any bone parameter. CONCLUSIONS: Tibial bone CSA is increased in children with NS. We speculate that this is a compensatory response to increased body weight. Defects in trabecular BMD were not identified in this cohort of children with NS.

Maternal plasma polyunsaturated fatty acid status in late pregnancy is associated with offspring body composition in childhood.

CONTEXT: Maternal diet during pregnancy has been linked to offspring adiposity, but it is unclear whether maternal polyunsaturated fatty acid (PUFA) status during pregnancy affects offspring body composition. OBJECTIVE: We investigated the associations between maternal plasma n-3 and n-6 PUFA status at 34 wk gestation and offspring body composition. DESIGN AND SETTING: A prospective United Kingdom population-based mother-offspring cohort, the Southampton Women's Survey (SWS), was studied. PARTICIPANTS: A total of 12,583 nonpregnant women were recruited into the SWS, among whom 1987 delivered a baby before December 31, 2003; 293 mother-child pairs had complete measurements of maternal plasma PUFA concentrations in late pregnancy and offspring body composition at both ages 4 and 6 yr. MAIN OUTCOMES MEASURED: We measured offspring body composition by dual-energy x-ray absorptiometry, yielding fat mass, lean mass, percentage fat mass, and percentage lean mass. Results are presented as ß-coefficients for standardized variables, therefore reflecting the sd change of the outcome for every 1 sd of the predictor. RESULTS: After adjustment for maternal factors and child factors including height and duration of breast-feeding, maternal plasma n-6 PUFA concentration positively predicted offspring fat mass at 4 yr (ß = 0.14 SD/SD; P = 0.01) and 6 yr (ß = 0.11 SD/SD; P = 0.04), but there was no association with offspring lean mass at either age (ß = 0.005 SD/SD, P = 0.89; and ß = 0.008 SD/SD, P = 0.81, respectively). Maternal plasma n-3 PUFA concentration was not associated with offspring fat mass at 4 yr (ß = 0.057 SD/SD; P = 0.34) or 6 yr (ß = 0.069 SD/SD; P = 0.21). Maternal plasma n-3 PUFA status was positively associated with offspring lean mass on univariate analysis (4 yr, ß = 0.11, P = 0.06; 6 yr, ß = 0.14; P = 0.02); however, this was confounded by a positive association with offspring height. CONCLUSIONS: This observational study suggests that maternal n-6 PUFA status during pregnancy might influence offspring adiposity in childhood.

Selective reduction in trabecular volumetric bone mineral density during treatment for childhood acute lymphoblastic leukemia.

During treatment of childhood acute lymphoblastic leukemia (ALL) fracture incidence is increased. Studies using DXA, which measures a composite of both trabecular and cortical BMD, have shown reduced BMD during treatment. We investigated changes in compartmental (cortical and trabecular) volumetric BMD (vBMD) and bone geometry using peripheral quantitative computed tomography. These outcomes were also analysed in relation to adiposity and treatment factors. Thirty nine patients with ALL (64% male, median age 7.2 years (4.1-16.9)) were compared to 34 healthy controls (50% male, median age 9.1 years (4.4-18.7)). DXA-derived age-specific standard deviation scores (SDS) of the lumbar spine (LS) and femoral neck (FN) were reduced in subjects with ALL compared to controls (p ≤ 0.01). This persisted following adjustment for body size using height-specific SDS (LS -0.72 ± 1.02 vs -0.18 ± 0.72, p=0.01; FN -1.53 ± 0.96 vs -0.74 ± 0.74, p=0.001) and bone mineral apparent density (BMAD) SDS (LS -0.76 ± 1.14 vs 0.04 ± 1.08, p=0.01; FN -1.63 ± 1.38 vs -0.16 ± 1.20, p<0.001). Radial and tibial trabecular vBMD was also reduced (196.5 ± 54.9 mg/cm(3) vs 215.2 ± 39.9 mg/cm(3), p=0.03 and 232.8 ± 60.3mg/cm(3) vs 267.5 ± 60.2mg/cm(3), p=0.002, respectively), but cortical vBMD at the radius and tibia was similar in patients and controls. A lowered tibial bone strength index (BSI) was identified in patients with ALL (53.9 ± 23.1mg/mm(4) vs 82.5 ± 27.8 mg/mm(4), p<0.001) suggesting lower fracture threshold from compressive forces. No relationships with measures of adiposity, duration of treatment or cumulative corticosteroid dose were identified. Our findings therefore suggest that reduction in trabecular vBMD during childhood ALL treatment may contribute to the observed increased fracture incidence and bony morbidity in this group.

Increased adiposity and altered adipocyte function in female survivors of childhood acute lymphoblastic leukaemia treated without cranial radiation.

BACKGROUND: Excess adiposity is a complication of childhood acute lymphoblastic leukaemia (ALL) and is commonly attributed to cranial radiation (CRT) administration. Hyperleptinaemia also occurs during ALL treatment, but there are no data on long-term alterations to adipocytokines following treatment without CRT. METHODS: Fifty-four survivors (50% female) and 51 controls (59% female) were recruited. Body composition assessment was by BMI, air displacement plethysmography (BODPOD), bioelectrical impedance analysis (BIA) and skinfold thickness (SFT). Fasting blood samples were analysed for adipocytokines (leptin, adiponectin, resistin, tumour necrosis factor-α, interleukin-6). RESULTS: The BMI standard deviation score (0.71 vs. 0.04, p < 0.05) and fat percentage measured by BIA (29.8% vs. 24.6%, p = 0.01) and SFT (31.7% vs. 28.2%, p = 0.007) were greater in female survivors compared with controls. Adiposity was similar in male survivors and controls. Absolute leptin (17.8 vs. 7.8 ng/ml, p = 0.01) and fat-adjusted leptin concentrations (p < 0.05) were higher in female survivors compared to controls. Female survivors were less insulin sensitive than controls (p = 0.02). These findings were not observed in males. There were no differences in the other adipocytokines between survivors and controls. CONCLUSIONS: Long-term unfavourable alterations to body composition and adipocyte function are observed in female, but not male, survivors of ALL treatment without CRT.

Growth monitoring following traumatic brain injury.

Hypopituitarism is an important consequence of traumatic brain injury (TBI). Growth monitoring can be used as an indicator of pituitary function in children. A retrospective audit of case notes of 123 children who required intensive care unit admission with TBI found that only 71 (33%) of 212 attendances in 38 of 85 children followed up had documented height and weight measurements. Children were reviewed in 11 different specialty clinics, which showed a wide variation in the frequency of growth monitoring. Serial growth measurements were available for only 22 patients (17%), which showed a reduction in height standard deviation scores (0.17 (SD 0.33), p = 0.017) over a mean follow-up period of 25.2 (SD 21.6) months. In conclusion, growth monitoring following TBI was poorly performed in this cohort, highlighting the need for a co-ordinated approach by primary and secondary care and all departments in tertiary centres involved in the follow-up of children with TBI.

The addition of metformin in type 1 diabetes improves insulin sensitivity, diabetic control, body composition and patient well-being.

AIM: As many overweight people with T1DM are insulin resistant, adjuvant therapy with insulin sensitising agents, such as metformin, may be beneficial. This study evaluated the effect of adjuvant metformin in T1DM on insulin sensitivity, diabetic control, body composition, quality of life (QOL) and treatment satisfaction. MATERIALS AND METHODS: A 3-month prospective open-labelled pilot study of 16 patients aged 18-40 with T1DM and body mass index (BMI) >25 kg/m(2) was performed. The patients received 500-850 mg metformin twice daily. Insulin sensitivity, assessed by a frequently sampled intravenous glucose tolerance test [n=5], body composition, HbA(1c) and quality of life (QOL) were measured before and after treatment. A retrospective review of 30 patients with T1DM treated with metformin for at least 4 months was also performed. BMI, HbA(1c) and insulin requirements during metformin treatment was compared to pre-metformin data, and to patients treated with insulin only. RESULTS: In the pilot study, insulin sensitivity increased significantly from 0.86 +/- 0.33 x 10(-4)/min/(microU/ml) to 1.17 +/- 0.48 x 10(-4)/min/(microU/ml) after 3 months adjuvant therapy (p = 0.043). This was associated with a decreased insulin requirement and mean daily blood glucose. There were no significant changes in HbA(1c) or body composition. QOL significantly improved (p < 0.002). The retrospective review revealed an initial reduction in HbA(1c) (0.8 +/- 1.4%, p = 0.001). This effect diminished with prolonged treatment. BMI decreased in patients remaining on metformin for a 2-year period (0.5 +/- 0.5kg/m(2), p = 0.042). CONCLUSION: Adjuvant metformin can improve QOL, insulin sensitivity and glycaemic control in overweight adults with T1DM.

In vitro and in vivo association and subcellular distribution of toxic and experimentally modified endotoxin.

Cell association and organ distribution of toxic and experimentally modified endotoxin were compared in whole animals and hepatoma tissue culture (HTC) cells. For both toxic and poly-l-alpha-ornithine mixed endotoxin in vivo, most of the endotoxin becomes associated with the reticuloendothelial system (RES) rich organs. Organ distribution does not change from 1 to 5 h. Significantly less detoxified endotoxin becomes associated with RES-rich organs. Association and nuclear transfer of toxic endotoxin in HTC cells are gradual and time-dependent processes. Plasma treatment increased association of endotoxin with HTC cells. Poly-l-alpha-ornithine (4 micrograms/mL) also significantly increases HTC cell association of endotoxin, and nuclear transfer of endotoxin was similar in principle to the toxic material. Association of detoxified endotoxin with HTC cells is significantly higher than toxic endotoxin and increases with time. In contrast with toxic and poly-l-alpha-ornithine mixed endotoxin, nuclear association of alkaline-treated detoxified endotoxin did not increase significantly during 5 h incubation. Cumulatively, these observations indicate that while tissue culture cells could provide a more controllable experimental system by which to study the fate and pathogenic mechanism of endotoxin at the cellular and subcellular level, HTC cells under the conditions employed herein do not yield binding data which compare favorably with in vivo results. Caution must be exercised when extrapolating in vitro data to the actual in vivo action of endotoxin.

Association of type 1 pili with the ability of livers to clear Salmonella typhimurium.

The role of type 1 pili in the adherence of Salmonella typhimurium strain SR-11 to hepatic sinusoidal cells was investigated. An average of 66.7% of piliated organisms was cleared by perfused livers on a single pass. Mannose and alpha-methyl-D-mannoside inhibited such trapping in a dose-dependent manner. Preincubation of the bacteria, but not the liver, with either sugar also inhibited trapping, suggesting that the sugar binds to bacterial, not hepatic, receptors. Significant numbers of previously trapped bacteria could be eluted by adding mannose to the wash medium. Bacteria with reduced piliation, obtained either by growing bacteria on agar or by using a nonpiliated variant of the parent strain, were trapped to a significantly lesser extent than the parent strain. The liver appears to selectively trap heavily piliated organisms since reperfusion of bacteria through a second liver results in significantly less trapping than occurs with the first perfusion. In vivo, the nonpiliated variant strain was cleared much more slowly than the piliated parent strain. Mannose and alpha-methyl-D-mannoside, but not glucose, decreased clearance rates of piliated organisms. Cumulatively, the data suggest that type 1 pili are a major factor in hepatic clearance of S. typhimurium.

Retention of Plasmodium berghei sporozoites within perfused mouse livers.

A mouse liver perfusion model was adapted to evaluate the efficiency of the liver in retaining Plasmodium berghei sporozoites. Specific numbers of sporozoites were perfused into each liver via a portal vein cannula. The numbers of sporozoites in the perfusate effluent were counted and the percent sporozoite retention calculated. Over 95% of sporozoites suspended in medium with plasma were retained in a normal liver following a single passage. Sporozoites were seen in sinusoids of perfused livers using scanning electron microscopy. This liver perfusion model offers a valuable method to help clarify sporozoite interactions with elements of the liver.

Clearance and killing of Candida albicans in the perfused mouse liver.

Hepatic interactions of C. albicans with perfused mouse livers were characterized and compared in normal and glucan-treated mice. Normal livers, in the absence of serum, trapped greater than 90% and killed greater than 20% of the infused yeast. Phenylbutazone had no effect. Silica treatment abolished killing and decreased trapping suggesting that candidicidal activity of the liver is mediated by Kupffer cells. Immune serum, but not normal serum, enhanced trapping and killing in normal livers. Liver hypertrophy was evident in mice treated with glucan, but no enhanced candidicidal activity was observed in the absence of humoral factors. Specific immune serum and normal serum increased killing of C. albicans in glucan stimulated liver, suggesting a requirement for serum opsonin in facilitating glucan enhanced killing. Specific immune serum potentiated the greatest increase in killing. Glucan treatment in conjunction with immune serum increased killing to approximately 40%. D-mannose, but not D-glucose or D-mannitol impaired trapping of the yeast in livers of normal mice. Together, the data suggest that hepatic trapping of C. albicans involves phagocytic events as well as interactions of the yeast with surface receptors on sinusoidal cells and support the role for the liver in restricting hematogenous dissemination of C. albicans in the infected host.

Trapping and killing of Candida albicans by Corynebacterium parvum-activated livers.

Corynebacterium parvum vaccination significantly increased the number of leukocytes adherent to hepatic vessels. Perfused C. parvum-treated livers killed significantly more Candida albicans than did livers not treated with C. parvum, an effect reversed by the macrophage inhibitors silica, phenylbutazone, and iodoacetate.

Role of Kupffer cells, complement, and specific antibody in the bactericidal activities of perfused livers.

The relative roles of Kupffer cells, complement, and specific antibody in liver antimicrobial activities were investigated by using a rat liver perfusion model. Normal livers trapped an average of 60% of Salmonella typhimurium in a single pass and in the presence of plasma killed more than 60% of these organisms in 30 min. Livers depleted of Kupffer cell function by silica treatment had significantly less bactericidal ability (ca. 15%) in the presence of plasma, showing that viable Kupffer cells are required for optimal antimicrobial activity. To determine the importance of complement in Salmonella killing, plasma complement activity was inhibited by heating at 57 and 50 degrees C, zymosan absorption, chelation with disodium ethylenediaminetetraacetate (EDTA) and depletion of rat C3 by using specific immunoabsorbent. All treatments significantly reduced bactericidal activity in the perfused liver. Chelation of plasma with EDTA had no effect, suggesting that the alternate and not the classical pathway for complement activation was involved. Immune plasma alone was bactericidal. When immune plasma was heated, zymosan absorbed, or chelated with EDTA, bactericidal activity was inhibited in the perfused liver, but bacterial trapping increased. These results suggest that complement is required for bactericidal activity in perfused livers and that specific antibody only enhances bacterial trapping.

Physiological and metabolic alterations accompanying systemic candidiasis in mice.

Mice challenged intravenously with 10(6) viable Candida albicans died between 1 and 16 days after infection. Near the time of death, over 98% of the recoverable fungi came from the kidneys. Physiologically, animals were in renal failure near the time of death as evidenced by elevated blood urea nitrogen (BUN) and blood creatinine levels and a creatinine clearance rate which was about one-half normal. No abnormalities in liver glucogen and blood glucose levels were detectable. When mice were challenged with 4.5 X 10(6) viable C. albicans, they all died within 12 h. Near the time of death they had normal BUN values and were hyperglycemic. In mice receiving 4.5 X 10(6) heat-killed C. albicans, no deaths occurred and liver glycogen, blood glucose, and BUN levels all remained within a normal range and were different from responses to bacterial endotoxin. Cumulatively, the results demonstrate two distinct syndromes for the pathogenesis of experimental C. albicans infections. At the lower dose, mice were in renal failure associated with progressive renal infection. At the higher dose, renal failure was not observed. If a toxin was associated with death from the latter dose, it was not similar to bacterial endotoxin.