Recommendations for High-resolution Peripheral Quantitative Computed Tomography Assessment of Bone Density, Microarchitecture, and Strength in Pediatric Populations.

PURPOSE OF REVIEW: The purpose of this review is to summarize current approaches and provide recommendations for imaging bone in pediatric populations using high-resolution peripheral quantitative computed tomography (HR-pQCT). RECENT FINDINGS: Imaging the growing skeleton is challenging and HR-pQCT protocols are not standardized across centers. Adopting a single-imaging protocol for all studies is unrealistic; thus, we present three established protocols for HR-pQCT imaging in children and adolescents and share advantages and disadvantages of each. Limiting protocol variation will enhance the uniformity of results and increase our ability to compare study results between different research groups. We outline special cases along with tips and tricks for acquiring and processing scans to minimize motion artifacts and account for growing bone. The recommendations in this review are intended to help researchers perform HR-pQCT imaging in pediatric populations and extend our collective knowledge of bone structure, architecture, and strength during the growing years.

Effect of high-dose cholecalciferol (vitamin D3) on bone and body composition in children and young adults with HIV infection: a randomized, double-blind, placebo-controlled trial.

It is unknown whether vitamin D supplementation positively impacts body composition and bone outcomes in children and young adults with HIV. This RCT found that despite increasing 25(OH)D concentrations, high dose vitamin D3 supplementation did not impact bone or body composition in children and young adults with HIV infection. INTRODUCTION: The objective of this paper was to determine the impact of high-dose daily cholecalciferol (vitamin D3) supplementation on body composition and bone density, structure, and strength in children and young adults with perinatally acquired (PHIV) or behaviorally acquired (BHIV) HIV infection. METHODS: Participants were randomized to receive vitamin D3 supplementation (7000 IU/day) or placebo for 12 months. Serum 25-hydroxyvitamin D [25(OH)D] concentrations, dual energy X-ray absorptiometry (DXA) of the whole body and lumbar spine, and peripheral quantitative computed tomography (pQCT) of tibia sites were acquired at 0, 6, and 12 months. DXA and pQCT outcomes were expressed as sex- and population-ancestry specific Z-scores relative to age and adjusted for height or tibia length, as appropriate. RESULTS: Fifty-eight participants (5.0 to 24.9 years) received vitamin D3 supplements (n = 30) or placebo (n = 28). At enrollment, groups were similar in age, sex, population ancestry, growth status, serum 25(OH)D concentrations, body composition, and size-adjusted bone measures. Median 25(OH)D concentrations were similar (17.3 ng/mL in the vitamin D3 supplementation group vs 15.6 ng/mL in the placebo group), and both groups had mild bone deficits. At 12 months, 25(OH)D rose significantly in the vitamin D supplementation group but not in the placebo group (26.4 vs 14.8 ng/mL, respectively, p < 0.008). After adjusting for population ancestry, sex, antiretroviral therapy use, and season, there were no significant treatment group differences in bone or body composition outcomes. CONCLUSIONS: Despite increasing 25(OH)D concentrations, 12 months of high-dose vitamin D3 supplementation did not impact bone or body composition in children and young adults with HIV infection.

Musculoskeletal health in newly diagnosed children with Crohn's disease.

We evaluated the impact of Crohn's disease on muscle and bone strength, mass, density, and geometry in children with newly diagnosed CD and found profound muscle and bone deficits; nevertheless, the prevalence of vertebral fractures at this time point was low. INTRODUCTION: Crohn's disease (CD) is an inflammatory condition of the gastrointestinal tract that can affect the musculoskeletal system. The objective of this study was to determine the prevalence of vertebral fractures and the impact of CD on muscle and bone mass, strength, density, and geometry in children with newly diagnosed CD. METHODS: Seventy-three children (26 girls) aged 7.0 to 17.7 years were examined within 35 days following CD diagnosis by lateral spine radiograph for vertebral fractures and by jumping mechanography for muscle strength. Bone and muscle mass, density, and geometry were assessed by dual-energy x-ray absorptiometry and peripheral quantitative computed tomography (pQCT). RESULTS: Disease activity was moderate to severe in 66 (90%) patients. Mean height (Z-score -0.3, standard deviation (SD) 1.1, p = 0.02), weight (Z-score -0.8, SD 1.3, p < 0.01), body mass index (Z-score -1.0, SD 1.3, p < 0.01), lumbar spine areal bone mineral density (BMD; Z-score -1.1, SD 1.0, p < 0.01), total body bone mineral content (Z-score -1.5, SD 1.0, p < 0.01), and total body lean mass (Z-score -2.5, SD 1.1, p < 0.01) were all low for age and gender. pQCT showed reduced trabecular volumetric BMD at the tibial metaphysis, expansion of the bone marrow cavity and thin cortices at the diaphysis, and low calf muscle cross-sectional area. Jumping mechanography demonstrated low muscle power. Only one patient had a vertebral fracture. CONCLUSIONS: Children with newly diagnosed CD have profound muscle and bone deficits; nevertheless, the prevalence of vertebral fractures at this time point was low.

Skeletal outcomes by peripheral quantitative computed tomography and dual-energy X-ray absorptiometry in adolescent girls with anorexia nervosa.

We conducted the first comparison of dual-energy X-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT) outcomes in adolescent girls with anorexia nervosa. We observed deficits in bone density by both tools. pQCT assessments were associated with many of the same clinical parameters as have been previously established for DXA. INTRODUCTION: Adolescents with anorexia nervosa (AN) commonly exhibit bone loss, but effects on bone geometry are less clear. We compared measures obtained by DXA and pQCT in girls with AN. METHODS: Seventy females (age 15.5 ± 1.9 years ) with AN and 132 normal-weighted controls underwent tibial measures by pQCT including trabecular volumetric bone mineral density (vBMD) at the 3 % site, cortical vBMD and dimensions at the 38 % site, and muscle cross-sectional area (CSA) at the 66 % site. Participants with AN also underwent standard DXA measures. Independent t tests compared the pQCT results, while Pearson coefficient assessed correlations among DXA and pQCT measures. RESULTS: Trabecular vBMD Z-scores were lower in AN compared to controls (AN -0.31 ± 1.42 vs +0.11 ± 1.01, p = 0.01) and cortical vBMD Z-scores were higher (AN +0.18 ± 0.92 vs -0.50 ± 0.88, p < 0.001). Trabecular vBMD and cortical CSA Z-scores positively correlated with DXA BMD Z-scores (r range 0.57-0.82, p < 0.001). Markers of nutritional status positively correlated with Z-scores for trabecular vBMD, cortical CSA, section modulus, and muscle CSA (p < 0.04 for all). CONCLUSIONS: This study is the first to compare DXA and pQCT measurements in adolescent girls with AN. We observed deficits in BMD by both DXA and pQCT. pQCT assessments correlated well with DXA bone and body composition measures and were associated with many of the same clinical parameters and disease severity markers as have been previously established for DXA. The differences in cortical vBMD merit further study.

Association of 25-hydroxyvitamin D with areal and volumetric measures of bone mineral density and parathyroid hormone: impact of vitamin D-binding protein and its assays.

UNLABELLED: A comparison of the association of different forms of 25-hydroxyvitamin D [25(OH)D] with parathyroid hormone (PTH) and with areal and volumetric bone mineral density (BMD) demonstrated that bioavailable and free 25(OH)D do not provide a better index of vitamin D status in terms of bone health compared to total 25(OH)D. INTRODUCTION: This study aims to compare measures of vitamin D-binding protein (DBP) using a monoclonal versus polyclonal ELISA and assess correlations of total versus estimated free and bioavailable 25(OH)D with BMD and PTH concentrations. METHODS: DXA and peripheral quantitative CT (pQCT) scans were obtained in 304 adults (158 black, 146 white), ages 21-80 years. Free and bioavailable 25(OH)D were calculated from total 25(OH)D, DBP, and albumin concentrations. Multivariable linear regression with standardized beta coefficients was used to evaluate associations of bone measures and PTH with total, free, and bioavailable 25(OH)D. RESULTS: Measures of DBP obtained using a monoclonal versus polyclonal ELISA were not correlated (r s = 0.02, p = 0.76). Free and bioavailable 25(OH)D based on the polyclonal assay were lower in black versus white participants (p < 0.0001); this race difference was not evident using the monoclonal assay. Adjusted for age, sex, calcium intake, and race, all forms of 25(OH)D were negatively associated with PTH, but the absolute coefficient was greatest for total 25(OH)D (-0.34, p < 0.001) versus free/bioavailable 25(OH)D (-0.18/-0.24 depending on DBP assay, p ≤ 0.003). In analyses stratified on race, none of the measures of 25(OH)D were associated with BMD across DXA and pQCT sites. CONCLUSIONS: The monoclonal versus polyclonal ELISA yielded highly discrepant measures of DBP, particularly among black individuals, likely related to established race differences in DBP polymorphisms. Contrary to prior studies, our findings indicate that using DBP to estimate bioavailable and free 25(OH)D does not provide a better index of vitamin D status in terms of bone health.

Increased risk of hip fracture associated with dually treated HIV/hepatitis B virus coinfection.

HIV and hepatitis B virus (HBV) infections are each associated with reduced bone mineral density, but it is unclear whether HIV/HBV coinfection is associated with an increased risk of fracture. We determined whether dually treated HIV/HBV patients had a higher incidence of hip fracture compared to treated HBV-monoinfected, antiretroviral therapy (ART)-treated HIV-monoinfected and HIV/HBV-uninfected patients. We conducted a cohort study among 4156 dually treated HIV/HBV-coinfected, 2053 treated HBV-monoinfected, 96,253 ART-treated HIV-monoinfected, and 746,794 randomly sampled uninfected persons within the US Medicaid populations of California, Florida, New York, Ohio and Pennsylvania (1999-2007). Coinfected patients were matched on propensity score to persons in each comparator cohort. Weighted survival models accounting for competing risks were used to estimate cumulative incidences and hazard ratios (HRs) with 95% confidence intervals (CIs) of incident hip fracture for dually treated coinfected patients compared to (i) HBV-monoinfected receiving nucleos(t)ide analogue or interferon alfa therapy, (ii) HIV-monoinfected on ART and (iii) uninfected persons. Dually treated coinfected patients had a higher cumulative incidence of hip fracture compared to ART-treated HIV-monoinfected (at 5 years: 1.70% vs 1.24%; adjusted HR, 1.37 [95% CI, 1.03-1.83]) and uninfected (at 5 years: 1.64% vs 1.22%; adjusted HR, 1.35 [95% CI, 1.03-1.84]) persons. The cumulative incidence of hip fracture was higher among coinfected than treated HBV-monoinfected patients (at 5 years: 0.70% vs 0.27%), but this difference was not statistically significant in competing risk analysis (adjusted HR, 2.62 [95% CI, 0.92-7.51]). Among Medicaid enrollees, the risk of hip fracture was higher among dually treated HIV/HBV-coinfected patients than ART-treated HIV-monoinfected and uninfected persons.

Use of proton pump inhibitors is associated with fractures in young adults: a population-based study.

UNLABELLED: Proton pump inhibitors (PPIs) are associated with risk for fracture in osteoporotic adults. In this population-based study, we found a significant association between PPIs and fracture in young adults, with evidence of a dose-response effect. Young adults who use PPIs should be cautioned regarding risk for fracture. INTRODUCTION: Proton pump inhibitors (PPIs) are associated with fracture in adults with osteoporosis. Because PPI therapy may interfere with bone accrual and attainment of peak bone mineral density, we studied the association between use of PPIs and fracture in children and young adults. METHODS: We conducted a population-based, case-control study nested within records from general medical practices from 1994 to 2013. Participants were 4-29 years old with ≥ 1 year of follow-up who lacked chronic conditions associated with use of long-term acid suppression. Cases of fracture were defined as the first incident fracture at any site. Using incidence density sampling, cases were matched with up to five controls by age, sex, medical practice, and start of follow-up. PPI exposure was defined as 180 or more cumulative doses of PPIs. Conditional logistic regression was used to estimate the odds ratio and confidence interval for use of PPIs and fracture. RESULTS: We identified 124,799 cases and 605,643 controls. The adjusted odds ratio for the risk of fracture associated with PPI exposure was 1.13 (95% CI 0.92 to 1.39) among children aged < 18 years old and 1.39 (95% CI 1.26 to 1.53) among young adults aged 18-29 years old. In young adults but not children, we observed a dose-response effect with increased total exposure to PPIs (p for trend <0.001). CONCLUSIONS: PPI use was associated with fracture in young adults, but overall evidence did not support a PPI-fracture relationship in children. Young adults who use PPIs should be cautioned regarding potentially increased risk for fracture, even if they lack traditional fracture risk factors.

The impact of vitamin D3 supplementation on muscle function among HIV-infected children and young adults: a randomized controlled trial.

OBJECTIVES: We tested the hypothesis that daily vitD3 supplementation increases neuromuscular motor skills, jump power, jump energy, muscular force, and muscular strength. METHODS: This was a secondary analysis of a randomized controlled trial of 12-months of oral 7,000 IU/day vitD3 supplementation or placebo among 56 persons living with HIV aged 9-25 years. Neuromuscular motor skills were quantified using the Bruininks-Oseretsky Test of Motor Proficiency. Power was quantified using peak jump power, and energy was quantified using peak jump height. Muscular force was quantified using isometric ankle plantar- and dorsiflexion, isokinetic knee flexion and extension. Muscular strength was quantified using isometric handgrip strength. RESULTS: After 12-months, serum 25-hydroxyvitamin D [25(OH)D] was higher with supplementation versus placebo (ß=12.1 ng/mL; P<0.001). In intention-to-treat analyses, supplementation improved neuromuscular motor skills versus placebo (ß=1.14; P=0.041). We observed no effect of supplementation on jump power, jump energy, muscular force, or muscular strength outcomes versus placebo. CONCLUSIONS: Among HIV-infected children and young adults supplementation with daily high-dose vitD3 increased concentration of serum 25(OH)D and improved neuromuscular motor skills versus placebo.

Changes in DXA and quantitative CT measures of musculoskeletal outcomes following pediatric renal transplantation.

This prospective study evaluated changes in dual energy X-ray absorptiometry (DXA) whole body bone mineral content (WB-BMC) and spine areal bone mineral density (spine-BMD), and tibia quantitative computed tomography (QCT) trabecular and cortical volumetric BMD and cortical area in 56 children over 12 months following renal transplantation. At transplant, spine-BMD Z-scores were greater in younger recipients (<13 years), versus 898 reference participants (p < 0.001). In multivariate models, greater decreases in spine-BMD Z-scores were associated with greater glucocorticoid dose (p < 0.001) and declines in parathyroid hormone levels (p = 0.008). Changes in DXA spine-BMD and QCT trabecular BMD were correlated (r = 0.47, p < 0.01). At 12 months, spine-BMD Z-scores remained elevated in younger recipients, but did not differ in older recipients (≥ 13) and reference participants. Baseline WB-BMC Z-scores were significantly lower than reference participants (p = 0.02). Greater glucocorticoid doses were associated with declines in WB-BMC Z-scores (p < 0.001) while greater linear growth was associated with gains in WB-BMC Z-scores (p = 0.01). Changes in WB-BMC Z-scores were associated with changes in tibia cortical area Z-scores (r = 0.52, p < 0.001), but not changes in cortical BMD Z-scores. Despite resolution of muscle deficits, WB-BMC Z-scores at 12 months remained significantly reduced. These data suggest that spine and WB DXA provides insight into trabecular and cortical outcomes following pediatric renal transplantation.

Changes in trabecular bone density in incident pediatric Crohn's disease: a comparison of imaging methods.

UNLABELLED: This study of changes in dual energy x-ray absorptiometry (DXA) spine BMD following diagnosis and treatment for childhood Crohn's disease demonstrated that changes in conventional posteroanterior BMD results were confounded by impaired growth, and suggested that lateral spine measurements and strategies to estimate volumetric BMD were more sensitive to disease and treatment effects. INTRODUCTION: We previously reported significant increases in peripheral quantitative CT (pQCT) measures of trabecular volumetric bone mineral density (vBMD) following diagnosis and treatment of pediatric Crohn's disease (CD). The objective of this study was to compare pQCT trabecular vBMD and three DXA measures of spine BMD in this cohort: (1) conventional posteroanterior BMD (PA-BMD), (2) PA-BMD adjusted for height Z (PA-BMDHtZ), and (3) width-adjusted volumetric BMD (WA-BMD) estimated from PA and lateral scans. METHODS: Spine DXA [lumbar (L1-4) for posteroanterior and L3 for lateral] and tibia pQCT scans were obtained in 65 CD subjects (ages 7-18 years) at diagnosis and 12 months later. BMD results were converted to sex, race, and age-specific Z-scores based on reference data in >650 children (ages 5-21 years). Multivariable linear regression models identified factors associated with BMD Z-scores. RESULTS: At CD diagnosis, all BMD Z-scores were lower compared with the reference children (all p values <0.01). The pQCT vBMD Z-scores (-1.46 ± 1.30) were lower compared with DXA PA-BMD (-0.75 ± 0.98), PA-BMDHtZ (-0.53 ± 0.87), and WA-BMD (-0.61 ± 1.10) among CD participants. Only PA-BMD Z-scores were correlated with height Z-scores at baseline (R = 0.47, p < 0.0001). pQCT and WA-BMD Z-scores increased significantly over 12 months to -1.04 ± 1.26 and -0.20 ± 1.14, respectively. Changes in all four BMD Z-scores were positively associated with changes in height Z-scores (p < 0.05). Glucocorticoid doses were inversely associated with changes in WA-BMD (p < 0.01) only. CONCLUSIONS: Conventional and height Z-score-adjusted PA DXA methods did not demonstrate the significant increases in trabecular vBMD noted on pQCT and WA-BMD scans. WA-BMD captured glucocorticoid effects, potentially due to isolation of the vertebral body on the lateral projection. Future studies are needed to identify the BMD measure that provides greatest fracture discrimination in CD.

Reduced fracture risk with early corticosteroid withdrawal after kidney transplant.

Corticosteroid use after kidney transplantation results in severe bone loss and high fracture risk. Although corticosteroid withdrawal in the early posttransplant period has been associated with bone mass preservation, there are no published data regarding corticosteroid withdrawal and risk of fracture. We hypothesized lower fracture incidence in patients discharged from the hospital without than with corticosteroids after transplantation. From the United States Renal Data System (USRDS), 77, 430 patients were identified who received their first kidney transplant from 2000 to 2006. Fracture incidence leading to hospitalization was determined from 2000 to 2007; discharge immunosuppression was determined from United Networks for Organ Sharing forms. Time-to-event analyses were used to evaluate fracture risk. Median (interquartile range) follow-up was 1448 (808-2061) days. There were 2395 fractures during follow-up; fracture incidence rates were 0.008 and 0.0058 per patient-year for recipients discharged with and without corticosteroid, respectively. Corticosteroid withdrawal was associated with a 31% fracture risk reduction (HR 0.69; 95% CI 0.59-0.81). Fractures associated with hospitalization are significantly lower with regimens that withdraw corticosteroid. As this study likely underestimates overall fracture incidence, prospective studies are needed to determine differences in overall fracture risk in patients managed with and without corticosteroids after kidney transplantation.

Special report on the 2007 adult and pediatric Position Development Conferences of the International Society for Clinical Densitometry.

The International Society for Clinical Densitometry (ISCD) conducts Position Development Conferences (PDCs) for the purpose of establishing standards and guidelines in the field of bone densitometry. Topics for consideration are selected according to clinical relevance, a perceived need for standardization, and the likelihood of achieving agreement. Questions regarding nomenclature, indications, acquisition, analysis, quality control, interpretation, and reporting of bone density tests for each topic area are assigned to task forces for a comprehensive review of the scientific literature. The findings of the review and recommendations are then presented to an international panel of experts at the PDC. The expert panel votes on potential Official Positions for appropriateness, necessity, quality of the evidence, strength of the recommendation, and applicability (worldwide or variable according to local requirements). Recommendations that are approved by the ISCD Board of Directors become Official Positions. The first Pediatric PDC was 20-21 June 2007 in Montreal, QC, Canada. The most recent Adult PDC was held 20-22 July 2007, in Lansdowne, VA, USA. This Special Report summarizes the methodology of the ISCD PDCs and presents selected Official Positions of general interest.

Altered chemokine receptor profile on circulating leukocytes in human heart failure.

Chemokines and their receptors have been implicated in the pathogenesis of different forms of heart failure (HF). We examined CC- and CXC-chemokine receptor expression in fresh peripheral blood leukocyte populations from 24 end-stage HF patients consisting of coronary artery disease (CAD; n = 6) and hypertrophic cardiomyopathy (HCM; n = 7) or idiopathic dilated cardiomyopathy (IDCM; n = 8) or valvular disease (VD; n = 3) and compared the data with 18 healthy controls. Levels of CCR1, 2, 3, 4, 5, and 7, and CXCR1, 2, 3, and 4 were measured by flow cytometry, and the expression profile was assessed as molecules of equivalent soluble fluorochrome units as well as frequency (percentage) of CD3+, CD4+, and CD8+ T cells and monocytes or granulocytes. Frequency of CD3+ CXCR4+, CD3+ CXCR1+, and CD3+ CXCR3+ cells was significantly increased in HF patients, whereas only CCR7 and CXCR4 expression levels were elevated on CD3+ cells. Both CD4+ CXCR4+ and CD8+ CXCR4+ cell frequencies were significantly increased irrespective of cardiac disease etiology. Elevated CCR7 expression was less pronounced on CD4+ than CD8+ cells in patients with CAD and IDCM. Expression of CXCR4 on CD8+ cells was upregulated substantially, regardless of the cause of disease. CD8+ CXCR1+ and CD8+ CXCR3+ but not CD4+ CXCR1+ or CD4+ CXCR3+ cells were increased in the HF patients with IDCM and CAD, respectively. Expression of CXCR1 or CXCR3 on both CD4+ and CD8+ cells did not differ in all the groups. For monocytes, frequency of CD14+ CCR1+ and CD14+ CCR2+ cells was significantly decreased in CAD patients, whereas, increase in CD14+ CXCR4+ cell frequency was accompanied with elevated CXCR4 expression. On granulocytes, CXCR1 and CXCR2 receptors were downregulated in all patients, compared with controls. Our results suggest that the altered expression profile of CC- and CXC-chemokine receptors on circulating leukocyte populations involves enhanced activation of the immune system, perhaps as part of the pathogenic mechanisms in HF. Modulation of the chemokine network could offer interesting novel therapeutic modalities for end-stage HF.

FTY720 treatment of kidney transplant patients: a differential effect on B cells, naïve T cells, memory T cells and NK cells.

FTY720 alters lymphocyte recirculation and homing by interfering with S1P receptors on lymphocytes, possibly in combination with chemokine receptors, and induces a decrease in PBL counts. In fresh, whole blood samples of 14 kidney transplant patients, we analyzed by flow cytometry the effect of FTY on the number of NK cells, monocytes, naïve (CCR7+) T cells, memory (CCR5+) T cells and B cells. Patients treated with 0.5, 2.5 or 5mg FTY/day showed a strong decrease in T and B cell numbers. NK cells and monocytes were not affected. FTY reduced primarily naïve T cells. From the memory T cells (CCR5+), predominantly CD8 cells, 40-60% remained in the circulation. The majority of the CCR7+ cells disappeared from the circulation within 3-6h, while a further reduction was achieved later. The more slowly decrease in naïve CCR7+ T cell numbers was also observed in the group treated with 0.25mg FTY/day. Elispot assays revealed no IL-4 producing cells and a low frequency of IFN-gamma producing cells. We suggest that both CCR7 dependent and independent mechanisms are involved in the depletion of T cells from peripheral blood.

Impaired circulating dendritic cell reconstitution identifies rejecting recipients after clinical heart transplantation independent of rejection therapy.

OBJECTIVE: Dendritic cell (DC) mediated allo-antigen presentation to host antigen specific T-lymphocytes initiates acute allograft rejection. We investigated peripheral blood DC (PBDC) incidence and DC subset reconstitution in relation to histological diagnosis of acute cellular rejection (AR) and administration of rejection therapy after clinical heart transplantation (post-HTx). METHODS: Venous blood from 20 HTx recipients under standard immunosuppression was collected during serial endomyocardial biopsy (EMB) prior to administration of rejection therapy in a 9-month follow-up post-HTx. Echocardiographic assessment of allograft function during EMB was performed to distinguish clinical necessity for rejection therapy within histologically rejecting patients (R). Myeloid (mDC) and plasmacytoid (pDC) subsets identified by flow-cytometry were analysed for different ISHLT rejection grades. Circulating PBDC incidence and mDC/pDC ratio were compared sequentially between non-rejecting (NR) recipients and R patients treated (3A(+)) or not-treated (3A(-)) with rejection therapy during follow-up. RESULTS: Eleven samples from biopsy-proven AR episodes (AR(+): ISHLT>or=3) were compared to 89 samples from non-rejection episodes (AR(-): ISHLT grade 0, n=52; grade 1, n=29; grade 2, n=8). We observed an inverse correlation of mDCs (P<0.05) but not pDCs with increasing rejection grade. PBDC incidence and mDC/pDC ratio were low in blood samples obtained during AR (P<0.05 and P<0.01, respectively). Both PBDCs and mDC/pDC ratio decreased during each AR episode (P<0.05). Comparison of 3A(+) and 3A(-) rejectors with NR patients after 12 weeks post-HTx revealed lower PBDC incidence (P<0.01) and mDC/pDC ratio (P<0.05) for R patients, independent of rejection therapy. CONCLUSIONS: Defective DC subset reconstitution by dendritic cell profiling identifies patients at risk for AR after 3 months post-HTx. This finding may contribute to further optimization of immunosuppressive treatment strategies after clinical heart transplantation.

Evaluation of low density spine software for the assessment of bone mineral density in children.

Pediatric dual-energy X-ray absorptiometry spine scans often cannot be analyzed with standard software due to a failure to identify the bone edges of low density vertebrae. Low density spine (LDS) software improves bone detection compared with standard software. The objective of this study was to compare bone mineral density (BMD) measurements obtained with the standard and LDS software in 27 healthy nonobese, 32 obese, and 41 chronically ill children, ages 2-18 years. Lumbar spine (L1-L4) BMD, measured by standard analysis, ranged from 0.531-1.244 gm/cm2. Reanalysis with the LDS software resulted in a systematic increase (mean +/- SD) in estimated bone area of 17.0+/-5.0%, an increase in bone mineral content of 6.1+/-6.3%, and a mean decrease in BMD of 8.7+/-1.7% (all p < 0.001). This resulted in a mean decrease in BMD Z score of 0.7+/-0.2. Linear regression models, predicting standard BMD from LDS BMD, were fit for the three subject groups (R2 = 0.993-0.995). Small differences in slopes were detected across groups (p = 0.07); LDS BMD predicted higher standard BMD in obese subjects. In conclusion, LDS analysis resulted in a clinically significant decrease in measured BMD. The association between analysis methods was exceptionally high (R2 > 0.99), indicating that LDS BMD accurately predicts standard BMD. Although LDS BMD in obese subjects predicts higher standard BMD results than in nonobese subjects, the small difference is of questionable clinical significance. LDS software is a useful tool for the assessment of BMD in children.

Early risk factors for increased adiposity: a cohort study of African American subjects followed from birth to young adulthood.

BACKGROUND: Obesity is an increasing concern in the United States. Effective prevention of obesity requires the risk factors to be well defined. African Americans have a high risk of obesity. OBJECTIVE: The objective of this study was to identify risk factors, present at birth, for increased adiposity in adulthood in an African American population. DESIGN: In this retrospective analysis of a prospective cohort study, anthropometric and socioeconomic variables were collected at birth. A representative sample of 447 African American subjects was followed up until young adulthood, when skinfold thickness was measured. Associations between the independent variables and increased adiposity (skinfold thickness above the 85th percentile) were explored by using unadjusted and adjusted analyses. RESULTS: Three variables measured at birth were independently associated with adiposity in young adulthood, explaining 12% of the variance. The odds ratios (with 95% CIs) of these variables for increased adiposity were 2.7 (1.2, 6.2) for female sex, 4.0 (1.4, 11. 2) for first-born status, and 1.15 (1.06, 1.25) for each unit increment in maternal prepregnancy body mass index (BMI; in kg/m(2)). After adjustment for these variables, birth weight for gestational age and socioeconomic variables were not associated with adiposity. CONCLUSIONS: This cohort study of African American subjects was the first to identify first-born status as an independent risk factor for increased adiposity in adulthood in a US population. The results of the study strengthen previous reports of the effect of female sex and maternal BMI on adulthood obesity. Identification of risk factors early in life may help target prevention toward high-risk children and allow healthy lifestyles to be established before the onset of obesity.

Interaction between tacrolimus and chloramphenicol in a renal transplant recipient.

BACKGROUND: The metabolism of tacrolimus is influenced by several medications when they are given concurrently. We report the interaction between tacrolimus and chloramphenicol in a renal transplant recipient. METHODS: An adolescent with vancomycin-resistant Enterococcus was given standard doses of chloramphenicol. Tacrolimus trough levels increased, and the dose was adjusted to maintain the target trough level. Pharmacokinetic studies were obtained during chloramphenicol administration and 14 days after its discontinuation. RESULTS: Toxic levels of tacrolimus were seen on the second day of chloramphenicol administration, requiring an 83% reduction in the tacrolimus dose. The dose-adjusted area under the curve value for tacrolimus was 7.5-fold greater while the patient was on chloramphenicol. These data are consistent with inhibition of tacrolimus clearance by chloramphenicol CONCLUSIONS: Chloramphenicol interferes with tacrolimus metabolism. Careful monitoring of tacrolimus trough levels during concomitant chloramphenicol therapy is recommended to avoid toxicity.

Effects of the enantiomers of R,S-salbutamol on incompletely fused tetanic contractions of slow- and fast-twitch skeletal muscles of the guinea-pig.

1. The effects of racemic R,S-salbutamol, and its individual enantiomers have been studied on incompletely fused (sub-tetanic) contractile responses of fast- and slow-contracting isolated skeletal muscles of the guinea-pig. 2. R,S-salbutamol (2-4 microM) decreased the peak force of sub-tetani in the slow-contracting soleus muscle and increased the peak force of sub-tetani in the fast-contracting peroneus longus muscle. It also increased the force of the first twitch of sub-tetani in both muscles. The decrease in the peak force of sub-tetani in the soleus muscle was due to defusion of the individual twitches caused by a shortening of their time course. 3. The effects of 4 microM of the racemate on both fast- and slow-contracting muscles were mimicked by 2 microM R-salbutamol (levalbuterol). However, 2 microM S-salbutamol was devoid of activity in both muscles. 4. We concluded that all the effects of R,S-salbutamol on guinea-pig skeletal muscles are due to the activity of the R-enantiomer. Thus there is a common enantiomeric profile for the skeletal muscle and bronchorelaxant activity of the compound.

Vancomycin pharmacokinetics in very low birth weight neonates.

The pharmacokinetics of vancomycin hydrochloride was studied in 12 very low birth weight infants. The gestational age (mean +/- SD) was 25.9 +/- 1.3 weeks and body weight was 769.2 +/- 151.5 g at the time of initiation of the study. Vancomycin was infused over a period of 60 minutes in a dosage of 14.2 +/- 3.2 mg/kg once daily in 10 patients, twice daily in 1 patient and every 36 hours in 1 patient for a mean of 10.5 +/- 4.9 days. Serial blood samples were obtained and the concentration time data were fitted to a one-compartment open model using the ADAPT computer program. A significant positive correlation was found between postconceptional age and vancomycin clearance (P less than 0.005) and between vancomycin elimination half-life and plasma creatinine (P less than 0.01). A negative correlation existed between plasma creatinine and vancomycin clearance (P less than 0.005), between postconceptional age and plasma creatinine (P less than 0.005) and between vancomycin half-life and postconceptional age (P less than 0.01). On the basis of these findings a vancomycin dosage of 15 mg/kg every 24 hours for infants less than 1000 g should yield concentrations within the accepted therapeutic range. This susceptible population requires frequent monitoring of vancomycin concentrations because of the high degree of interpatient variability and the continuous maturation of renal function.