Attenuated maximal muscle strength and peak power in children with sickle cell disease

Dominant hand maximal handgrip strength evaluated with a handgrip dynamometer and peak power evaluated with a force plate, adjusted for body size and composition, were compared in African-American children aged 5 to 13 years, with and without type SS sickle cell disease (SCD-SS). Children with SCD-SS (n = 35; age, 9.0 ± 2.0 y) compared with healthy control children (n = 103; age, 8.6 ± 1.8 y) did not differ by age, sex, or pubertal status, yet had significantly lower Z scores for height, weight, body mass index, upper arm muscle area, upper arm fat area, fat mass-for-height and lean mass-for-height. Children with SCD-SS had significantly lower handgrip strength (12.7 ± 3.3 vs. 15.2 ± 5.1 kg, P < 0.008), peak power (882 ± 298 vs. 1167 ± 384 W, P < 0.001), and growth and body composition adjusted Z scores for handgrip strength (0.6 ± 1.3 standard deviations, P < 0.004) and peak power (male children = 1.0 ± 0.8 standard deviations, P < 0.0002; female children = 1.0 ± 1.7 standard deviations, P < 0.006). Maximal muscle strength and peak power are attenuated in children with SCD-SS compared with healthy control children beyond expectation for growth and body composition deficits suggesting that additional factors contribute to attenuation in anaerobic performance.     

Genetics of Bone Mass in Childhood and Adolescence: Effects of Sex and Maturation Interactions

We aimed to determine if adult bone mineral density (BMD) susceptibility loci were associated with pediatric bone mass and density, and if sex and pubertal stage influenced any association. We analyzed prospective areal BMD (aBMD) and bone mineral content (BMC) data from the Bone Mineral Density in Childhood Study (n = 603, European ancestry, 54% female). Linear mixed models were used to assess if 77 single‐nucleotide polymorphisms (SNPs) near known adult BMD susceptibility loci interacted with sex and pubertal stage to influence the aBMD/BMC; adjusting for age, BMI, physical activity, and dietary calcium. The strongest main association was observed between an SNP near C7orf58 and distal radius aBMD. However, this association had a significant sex?SNP interaction, revealing a significant association only in females (b = –0.32, p = 1.8 × 10^–6). Furthermore, the C12orf23 locus had significant interactions with both sex and pubertal stage, revealing associations in females during Tanner stage I for total hip aBMD (b = 0.24, p = 0.001) and femoral neck aBMD (b = 0.27, p = 3.0 × 10^–5). In contrast, the sex?SNP interactions for loci near LRP5 and WNT16 uncovered associations that were only in males for total body less head BMC (b = 0.22, p = 4.4 × 10^–4) and distal radius aBMD (b = 0.27, p = 0.001), respectively. Furthermore, the LRP5 locus interacted with both sex and pubertal stage, demonstrating associations that were exclusively in males during Tanner V for total hip aBMD (b = 0.29, p = 0.003). In total, significant sex?SNP interactions were found at 15 loci; pubertal stage?SNP interactions at 23 loci and 19 loci interacted with both sex and pubertal stage. In conclusion, variants originally associated with adult BMD influence bone mass in children of European ancestry, highlighting the fact that many of these loci operate early in life. However, the direction and magnitude of associations for a large number of SNPs only became evident when accounting for sex and maturation. © 2015 American Society for Bone and Mineral Research.     

Optimal monitoring time interval between DXA measures in children

The monitoring time interval (MTI) is the expected time in years necessary to identify a change between two measures that exceeds the measurement error. Our purpose was to determine MTI values for dual‐energy X‐ray absorptiometry (DXA) scans in normal healthy children, according to age, sex, and skeletal site. 2014 children were enrolled in the Bone Mineral Density in Childhood Study and had DXA scans of the lumbar spine, total hip, nondominant forearm, and whole body. Measurements were obtained annually for seven visits from 2002 to 2010. Annualized rates of change were calculated by age and sex for all bone regions. A subgroup of 155 children ages 6 to 16 years (85 boys) had duplicate scans for calculation of scan precision. The bone mineral density (BMD) regions of interest included the spine, total body less head (TBLH), total hip, femoral neck, and one‐third radius. Bone mineral content (BMC) was also evaluated for the spine and TBLH. The percent coefficient of variation (%CV) and MTI were calculated for each measure as a function of age and sex. The MTI values were substantially less than 1 year for the TBLH and spine BMD and BMC for boys ≤ 17 years and girls ≤ 15 years. The hip and one‐third radius MTIs were generally 1 year in the same group. MTI values as low as 3 months were found during the peak growth years. However, the MTI values in late adolescence for all regions were substantially longer and became nonsensical as each region neared the age for peak bone density. All four DXA measurement sites had reasonable (< 1 year) MTI values for boys ≤ 17 years and girls ≤ 15 years. MTI was neither useful nor stable in late adolescence and young adulthood. Alternative criteria to determine scan intervals must be used in this age range. © 2011 American Society for Bone and Mineral Research     

Genetic Risk Scores Implicated in Adult Bone Fragility Associate With Pediatric Bone Density

Using adult identified bone mineral density (BMD) loci, we calculated genetic risk scores (GRS) to determine if they were associated with changes in BMD during childhood. Longitudinal data from the Bone Mineral Density in Childhood Study were analyzed (N = 798, 54% female, all European ancestry). Participants had up to 6 annual dual energy X‐ray scans, from which areal BMD (aBMD) Z‐scores for the spine, total hip, and femoral neck were estimated, as well as total body less head bone mineral content (TBLH‐BMC) Z‐scores. Sixty‐three single‐nucleotide polymorphisms (SNPs) were genotyped, and the percentage of BMD‐lowering alleles carried was calculated (overall adult GRS). Subtype GRS that include SNPs associated with fracture risk, pediatric BMD, WNT signaling, RANK‐RANKL‐OPG, and mesenchymal stem cell differentiation were also calculated. Linear mixed effects models were used to test associations between each GRS and bone Z‐scores, and if any association differed by sex and/or chronological age. The overall adult, fracture, and WNT signaling GRS were associated with lower Z‐scores (eg, spine aBMD Z‐score: β_adult = –0.04, p = 3.4 × 10^?7; β_fracture = –0.02, p = 8.9 × 10^?6; β_WNT = –0.01, p = 3.9 × 10^?4). The overall adult GRS was more strongly associated with lower Z‐scores in females (p‐interaction ≤ 0.05 for all sites). The fracture GRS was more strongly associated with lower Z‐scores with increasing age (p‐interaction ≤ 0.05 for all sites). The WNT GRS associations remained consistent for both sexes and all ages (p‐interaction > 0.05 for all sites). The RANK‐RANKL‐OPG GRS was more strongly associated in females with increasing age (p‐interaction < 0.05 for all sites). The mesenchymal stem cell GRS was associated with lower total hip and femoral neck Z‐scores, in both boys and girls, across all ages. No associations were observed between the pediatric GRS and bone Z‐scores. In conclusion, adult identified BMD loci associated with BMD and BMC in the pediatric setting, especially in females and in loci involved in fracture risk and WNT signaling. © 2015 American Society for Bone and Mineral Research.     

Telephone Counseling for Patients with Chronic Heart Failure: Results of an Evaluation Study

Background

The effectiveness of a secondary prevention program for patients suffering from chronic heart failure (CHF) was evaluated.

Purpose

The program aimed at improving participants?? perceived health and actual physical symptoms. Insurants of a German health insurance company participated in a telephone counseling program with four modules focusing on dietary habits, physical activity, fluid intake, and medication compliance.

Method

Multilevel analyses were conducted to analyze changes in health related outcome variables over time in N?=?259 participants who completed the program in about 6?months.

Results

The results showed an improvement of perceived health status, physical symptoms, and somatic impairment. Furthermore, differential change was found when comparing ??finishers?? compared to ??non-finishers?? of specific modules indicating specific module effects.

Conclusion

The results are auspicious and, if sustained, are expected to bring about long-term health benefits for our study??s participants. The program proved to be applicable and well accepted in the sample of older, severely impaired CHF patients and effective in changing perceived health.     

The Poorly Membrane Permeable Antipsychotic Drugs Amisulpride and Sulpiride Are Substrates of the Organic Cation Transporters from the SLC22 Family

Variations in influx transport at the blood-brain barrier might affect the concentration of psychotropic drugs at their site of action and as a consequence might alter therapy response. Furthermore, influx transporters in organs such as the gut, liver and kidney may influence absorption, distribution, and elimination. Here, we analyzed 30 commonly used psychotropic drugs using a parallel artificial membrane permeability assay. Amisulpride and sulpiride showed the lowest membrane permeability (P_e < 1.5 × 10⁻⁶ cm/s) and will require influx transport to penetrate the blood-brain barrier and other physiological barriers. We then studied the uptake of amisulpride and sulpiride by the organic cation transporters of the SLC22 family OCT1, OCT2, OCT3, OCTN1, and OCTN2 Amisulpride was found to be transported by all five transporters studied. In contrast, sulpiride was only transported by OCT1 and OCT2. OCT1 showed the highest transport ability both for amisulpride (CL_int = 1.9 ml/min/mg protein) and sulpiride (CL_int = 4.2 ml/min/mg protein) and polymorphisms in OCT1 significantly reduced the uptake of both drugs. Furthermore, we observed carrier-mediated uptake that was inhibitable by known OCT inhibitors in the immortalized human brain microvascular endothelial cell line hCMEC/D3. In conclusion, this study demonstrates that amisulpride and sulpiride are substrates of organic cation transporters of the SLC22 family. SLC22 transporters may play an important role in the distribution of amisulpride and sulpiride, including their ability to penetrate the blood-brain barrier.

Electronic supplementary material

The online version of this article (doi:10.1208/s12248-014-9649-9) contains supplementary material, which is available to authorized users.KEY WORDS: amisulpride, blood-brain barrier, membrane permeability, organic cation transporters, sulpiride