The bone architecture is enhanced with combined PTH and alendronate treatment compared to monotherapy while maintaining the state of surface mineralization in the OVX rat

This study examined the effect of PTH and alendronate alone and in combination on the bone architecture, mineralization, and estimated mechanics in the OVX rat. Female Wistar rats aged 7-9months were assigned to one of five groups: (1) sham+vehicle, (2) OVX+vehicle, (3) OVX+PTH, (4) OVX+alendronate, and (5) OVX+PTH and alendronate. Surgery was performed at baseline (week 0), and biweekly treatment (15μg/kg of alendronate and/or daily (5days/week) 40μg/kg hPTH(1-34)) was administered from week 6 to week 14. Micro-CT scans of the right proximal tibial metaphysis were made in vivo at weeks 0, 6, 8, 10, 12 and 14 and measurements of bone microarchitecture and estimated mechanical parameters (finite element analysis) were made from the images. Synchrotron radiation micro-CT scans of the proximal tibia and fourth lumbar vertebrae were conducted ex vivo at the study endpoint to determine the degree and spatial distribution of the bone mineralization. Alendronate preserved the microarchitecture after OVX, and increased cortical (9%, p<0.05) and trabecular thickness (5%, p<0.05). PTH mono- and combined therapy induced increases in cortical (25-35%, p<0.05) and trabecular thicknesses (46-48%, p<0.05), resulting in a full restoration of bone volume in the PTH group, and an increase beyond baseline in the combined group. Improvements in estimated mechanical outcomes were observed in all treatment groups by the end of the study, with the combined group experiencing the greatest increase in predicted stiffness (63%, p<0.05). Alendronate treatment increased the peak mineral content above the other treatment groups at the trabecular (tibia: 6% above PTH, 6% above combined, L4: 4% above PTH, 4% above combined) and endocortical (tibia: 4% above PTH, 3% above combined, L4: 1% above PTH, 2% above combined) surfaces, while no differences in mineralization between the PTH and combined groups were observed. Combined treatment resulted in more pronounced improvements of the bone architecture than PTH monotherapy, while maintaining the state of mineralization observed with PTH treatment.     

The nicotinic acetylcholine receptors of zebrafish and an evaluation of pharmacological tools used for their study

Zebrafish (Danio rerio) have been used to study multiple effects of nicotine, for example on cognition, locomotion, and stress responses, relying on the assumption that pharmacological tools will operate similarly upon molecular substrates in the fish and mammalian systems. We have cloned the zebrafish nicotinic acetylcholine receptor (nAChR) subunits and expressed key nAChR subtypes in Xenopus oocytes including neuronal (α4β2, α2β2, α3β4, and α7) and muscle (α1β1_b?δ) nAChR. Consistent with studies of mammalian nAChR, nicotine was relatively inactive on muscle-type receptors, having both low potency and efficacy. It had high efficacy but low potency for α7 receptors, and the best potency and good efficacy for α4β2 receptors. Cytisine, a key lead compound for the development of smoking cessation agents, is a full agonist for both mammalian α7 and α3β4 receptors, but a full agonist only for the fish α7, with surprisingly low efficacy for α3β4. The efficacy of cytisine for α4β2 was somewhat greater than typically reported for mammalian α4β2. The ganglionic blocker mecamylamine was most potent for blocking α3β4 receptors, least potent for α7, and roughly equipotent for the muscle receptors and the β2-containing nAChR. However, the block of β2-containing receptors was slowly reversible, consistent with effective targeting of these CNS-type receptors in vivo. Three prototypical α7-selective agonists, choline, tropane, and 4OH-GTS-21, were tested, and these agents were observed to activate both fish α7 and α4β2 nAChR. Our data therefore indicate that while some pharmacological tools used in zebrafish may function as expected, others will not.     

Five-year outcome of state-wide hip surveillance of children and adolescents with cerebral palsy

This study reports the five-year outcomes of a prospective population-based study of clinical hip surveillance for children with cerebral palsy (CP) according to evidence-based standards of care. Systematic hip surveillance commenced in Queensland, Australia as a state-wide program in 2005. Queensland represents a dispersed population across a large geographical area, creating unique challenges in terms of service delivery. Over five years, 1,115 children with CP were recruited, representing 73% of the expected population based on 1.9 to 2.1 per 1,000 live births. Standardized clinical and radiological assessments have been provided, with a median follow-up of 1.2 years (range 1 month -5(+8) yrs). Of the 1,115 children, 423 (38%) have been discharged and 692 (62%) remain on surveillance with 314 (28%) identified as having hip displacement with Migration Percentage (MP) equal to or greater than 30% (≥ 30). The incidence of marked hip displacement (MP ≥ 30) was directly related to gross motor function, classified according to the gross motor function classification system (GMFCS), with distribution of GMFCS I=10, (3%), II=40 (13%), III=53 (43%), IV=96 (59%), and V=115 (64%). This state-wide surveillance program has been successful in correctly identifying children with hip displacement (MP ≥ 30), fast tracking children for orthopedic review and discharging those at minimal risk. No child has progressed to dislocation while on surveillance without orthopedic review.     

High resolution melting analysis for detection of BRAF exon 15 mutations in hairy cell leukaemia and other lymphoid malignancies

The BRAF V600E mutation has recently been described in all cases of hairy cell leukaemia (HCL). We have developed and validated a rapid and sensitive high-resolution melting analysis (HRMA) assay that detects BRAF exon 15 mutations when hairy cells are as low as 5-10% in a sample. All 48 HCL patients were positive for the BRAF V600E mutation, while 114 non-HCL cases were all V600E negative. Interestingly, we detected a novel BRAF D594N mutation in one patient with multiple myeloma. The HRMA assay offers a useful tool to aid the laboratory diagnosis of HCL.     

The relationship between adolescents' news media use and civic engagement: the indirect effect of interpersonal communication with parents

Using data from the 4-H Study of Positive Youth Development, a longitudinal study involving U.S. adolescents, multi-group structural equation modeling (SEM) was used to evaluate whether news media use is predictive of a set of civic indicators (civic duty, civic efficacy, neighborhood social connection, and civic participation) for youth in Grades 8, 9, and 10, via an indirect effect of interpersonal communication about politics with parents. The proposed model had a good fit within each grade. News media use was predictive of interpersonal communication with parents and in turn, interpersonal communication was predictive of civic duty, civic efficacy, neighborhood social connection, and civic participation. The cross-group comparison of the structural model suggests that the predictive qualities of news media use and interpersonal communication are comparable across grades. The role of media use and interpersonal communication in fostering civic development and socialization as well as implications for future research are discussed.     

Bone quality is partially recovered after the discontinuation of RANKL administration in rats by increased bone mass on existing trabeculae: an in vivo micro-CT study

Summary  

Bone loss and recovery in a receptor activator for nuclear factor κ B ligand (RANKL)-administered rat model was assessed. Microarchitecture, mineralization and strength deteriorated faster than ovariectomy (OVX). Recovery was dependent on the loss of trabecular elements and connections. Early recovery suggests a natural mechanism in rats to overcome excess RANKL, and may have implications for long-term bone loss.