Differential Bone Turnover in an Angulated Fracture Model in the Rat

We have developed a simple rat model of angulated tibial fracture which elicits substantial differences in bone formation and resorption within the same bone. In 35 rats the right mid-tibia was manually fractured and fixed with an intramedullary 17-gauge cannula needle. Twenty tibias were fixed in anterior angulation (27 ± 5°) and 15 in posterior angulation (31 ± 5°). Serial X-rays were taken over a 12-week period. All fractures healed completely within five weeks. In both groups, bone thickness was already significantly greater on the concave side than on the convex side at week 3 and remained so until the end of the experiment. The thickness on the convex side decreased dramatically within 3 to 5 weeks and gradually thereafter. For morphological analysis of bone mineralization, 3 rats from each group were given calcein and alizarin red injected at different time points up to 14 weeks. Maximum new bone formation was noted within the first 3 weeks. Over the ensuing weeks, new bone formation remained intense on the concave side, but it was virtually absent on the convex side. These results show that angulated fracture deformity reproducibly exhibits differential bone turnover, which can be exploited in research on local regulatory factors. To exemplify the utility of the model, an immunohistochemical study on two local markers was done. Callus tissue of five rats in the anterior angulation group at week 3 post-fracture was stained for the cytokine IL-1, a stimulator of bone resorption, and the neuropeptide CGRP, an inhibitor of resorption, showing clear differences in positive staining between the concave and convex sides. Our in-vivo model offers a means of analyzing morphologically and quantitatively the differential expression and action of factors involved in local bone turnover.     

Incidence of Hip Fracture in Romania and the Development of a Romanian FRAX Model

A FRAX^® model for Romania calibrated to the total Romanian population was released June 1, 2011. This article describes the data used to develop the Romanian FRAX model and illustrates its features compared to models for other countries. Age- and sex-stratified hip fracture incidence rates and mortality rates for 2010 were extracted from nationwide databases from the age of 40 years. For other major fractures, Romanian incidence rates were imputed, using Swedish ratios for hip to other major osteoporotic fracture (humerus, forearm, and clinically symptomatic vertebral fractures). Fracture incidence rates increased with increasing age: for hip fracture, incidence rates were higher among younger men than women but with a female preponderance from the age of 65 years. The 10-year probability of hip or major fracture was increased in patients with a clinical risk factor (CRF), lower BMI, female gender, higher age, and decreased BMD T score. Of the CRFs, a parental hip fracture accounted for the greatest increase in 10-year fracture probability. The Romanian FRAX tool is the first country-specific fracture prediction model. It is based on the original FRAX methodology, which has been externally validated in several independent cohorts. Despite some limitations, the strengths make the Romanian FRAX tool a good candidate for implementation into clinical practice.     

Entrainment of the Circadian Rhythm in Rat Pineal N-Acetyltransferase Activity Under Extremely Long and Short Photoperiods

Entrainment of a pacemaker driving the circadian rhythm in rat pineal N-acetyltransferase activity was studied under extremely long and short photoperiods. Adult male rats maintained under the light-dark regime (LD) 18:6 or under the regime LD 6:18 were exposed to a 1-min light pulse at different times at night, then they were released into darkness, and the next night phase-shifts of the evening N-acetyltransferase rise and of the morning N-acetyltransferase decline caused by light pulses were determined. The evening rise was phase-delayed by at most 0.5 h under LD 18:6, but by as much as 2.8 h under LD 6:18. The morning decline was phase-advanced by at most 1.9 h under LD 18:6, but by as much as 3.5 h under LD 6:18. Hence, the magnitude of phase-shifts and consequently patterns of phase-response curves, which show possibilities of discrete entrainment, depend on the photoperiods under which animals are maintained. A 1-min light pulse applied within 1 h before the end of the dark period phase-advanced the morning N-acetyltransferase decline under LD 18:6 as well as under LD 6:18, while a pulse applied within 1 h after the beginning of the dark period phase-delayed the evening N-acetyltransferase rise only in rats maintained under LD 18:6, but not in those kept under LD 6:18. It seems that under very long photoperiods, the N-acetyltransferase rhythm may be entrained by evening as well as by the morning light, while under very short photoperiods the rhythm may be synchronized by morning light only.     

Cerebrospinal fluid leakage after elective disc surgery

For patients undergoing elective disc herniation surgery the risk to experience a dural tear is somewhere around 1% both for the cervical and the thoracic regions and probably slightly higher for the lumbar region. In most cases a dural tear is diagnosed and taken care of peroperatively. When a leakage of cerebrospinal fluid is suspected postoperatively a combination of the patient’s history and imaging investigations/laboratory tests usually gives the diagnosis and it is mostly treated by closure in a new surgical procedure or by a subdural lumbar drainage. There is conflicting data on the long-term effect of a dural tear in relation to disc herniation surgery. This review exemplifies, describes and discusses how to diagnose, treat a dural tear and what the results are when dealing with it during or after disc herniation surgery.     

Rumination Moderates the Associations Between PTSD and Depressive Symptoms and Risky Behaviors in U. S. Veterans

Risky behaviors, including unsafe sex, aggression, rule breaking, self‐injury, and dangerous substance use have become a growing issue for U.S. veterans returning from combat deployments. Evidence in nonveteran samples suggests that risky behaviors reflect efforts to cope with and alleviate depressive and/or anxious symptoms, particularly for individuals with poor emotion‐regulation skills. These associations have not been studied in veterans. Rumination, or repeated thoughts about negative feelings and past events, is a coping strategy that is associated with several psychopathologies common in veterans. In this cross‐sectional study, 91 recently returned veterans completed measures of trait rumination, self‐reported risky behaviors, and symptoms of posttraumatic stress disorder (PTSD) and depression. Analyses revealed that veterans with more depressive and PTSD symptoms reported more risky behaviors. Moreover, rumination significantly interacted with PTSD symptoms and depressive symptoms (both β = .21, p < .05), such that psychiatric symptoms were associated with risky behaviors only for veterans with moderate to high levels of rumination. Although cross‐sectional, these findings support theory that individuals with poor coping skills may be particularly likely to respond to negative mood states by engaging in risky behaviors. Implications include using rumination‐focused interventions with veterans in order to prevent engagement in risky behaviors.     

Does osteoporosis therapy invalidate FRAX for fracture prediction?

Ten-year fracture risk assessment with the fracture risk assessment system (FRAX) is increasingly used to guide treatment decisions. Osteoporosis pharmacotherapy reduces fracture risk, but the effect is greater than can be explained from the increase in bone mineral density (BMD). Whether this invalidates fracture predictions with FRAX is uncertain. A total of 35,764 women (age ≥50 years) and baseline BMD testing (1996–2007) had FRAX probabilities retroactively calculated. A provincial pharmacy database was used to identify osteoporosis medication use. Women were categorized as untreated, current high adherence users [medication possession ratio (MPR) ≥0.80 in the year after BMD testing], current low adherence users (MPR <0.80), and past users. Fractures outcomes to 10 years were established form a population-based health data repository. FRAX and femoral neck BMD alone stratified major osteoporotic and hip fracture risk within untreated and each treated subgroup (all p-values <0.001) with similar area under the receiver operating characteristic curve. In untreated and each treated subgroup, a stepwise gradient in observed 10-year major osteoporotic and hip fracture incidence was found as a function of the predicted probability tertile (all p-values <0.001 for linear trend). Concordance (calibration) plots for major osteoporotic fractures and hip fractures showed good agreement between the predicted and observed 10-year fracture incidence in untreated women and each treated subgroup. Only in the highest risk tertile of women highly adherent to at least 5 years of bisphosphonate use was observed hip fracture risk significantly less than predicted, though major osteoporotic fracture risk was similar to predicted. In summary, this work suggests that the FRAX tool can be used to predict fracture probability in women currently or previously treated for osteoporosis. Although FRAX should not be used to assess the reduction in fracture risk in individuals on treatment, it may still have value for guiding the need for continued treatment or treatment withdrawal     

Denosumab reduces the risk of osteoporotic fractures in postmenopausal women, particularly in those with moderate to high fracture risk as assessed with FRAX

Denosumab has been shown to reduce the incidence of vertebral, nonvertebral, and hip fractures. The aim of the current study was to determine whether the antifracture efficacy of denosumab was dependent on baseline fracture probability assessed by FRAX. The primary data of the phase 3 FREEDOM study of the effects of denosumab in women with postmenopausal osteoporosis were used to compute country-specific probabilities using the FRAX tool (version 3.2). The outcome variable comprised all clinical osteoporotic fractures (including clinical vertebral fractures). Interactions between fracture probability and efficacy were explored by Poisson regression. At baseline, the median 10-year probability of a major osteoporotic fracture (with bone mineral density) was approximately 15% and for hip fracture was approximately 5% in both groups. In the simplest model adjusted for age and fracture probability, treatment with denosumab over 3 years was associated with a 32% (95% confidence interval [CI] 20% to 42%) decrease in clinical osteoporotic fractures. Denosumab reduced fracture risk to a greater extent in those at moderate to high risk. For example, at 10% probability, denosumab decreased fracture risk by 11% (p = 0.629), whereas at 30% probability (90th percentile of study population) the reduction was 50% (p = 0.001). The reduction in fracture was independent of prior fracture, parental history of hip fracture, or secondary causes of osteoporosis. A low body mass index (BMI) was associated with greater efficacy. Denosumab significantly decreased the risk of clinical osteoporotic fractures in postmenopausal women. Overall, the efficacy of denosumab was greater in those at moderate to high risk of fracture as assessed by FRAX.     

Cyclosporin A for the treatment of severe Henoch-Schönlein glomerulonephritis

We evaluated the efficacy of cyclosporin A (CyA) for treating pediatric patients with severe Henoch-Schönlein glomerulonephritis (HSP-GN) and nephrotic-range proteinuria. Seven pediatric HSP-GN patients (5 boys, 2 girls) were treated with CyA, with a mean age of 10.6 years at diagnosis (range 7.2–15.2 years) and mean follow-up times of 6.0 years (range 4.4–8.9 years) from diagnosis and 5.2 years (range 3.4–7.7 years) from the beginning of the CyA treatment. All had developed nephrotic-range proteinuria within 1–3 months of the HSP diagnosis. A renal biopsy was performed on all the patients, and two showed rapidly progressive glomerulonephritis. They all received additional angiotensin converting enzyme inhibitor medication and one to three types of immunosuppressive treatment had been tried in five of the seven patients before CyA was initiated at a mean interval of 0.7 years after diagnosis (range 0.1–2.0 years). All the patients responded to the CyA treatment within a mean of 1.4 months (range 1 week to 4 months). Four patients achieved a stable remission and had been without CyA treatment for a mean of 3.7 years (range 2.9–5.3 years) by the end of the follow-up. Three patients seemed to become CyA dependent, since they developed proteinuria when the treatment was stopped. CyA treatment had been started significantly earlier (P=0.045) in the former group (mean 0.2 years, range 0.1–0.3 years) than in the latter (mean 1.5 years, range 1.2–2.0 years). Renal function was preserved in all patients, the glomerular filtration rate, plasma cystatin C, serum albumin, and serum creatinine being within normal limits at the end of the follow-up. We conclude that CyA treatment for severe treatment-resistant HSP-GN is promising, since four of the seven patients enjoy stable remission and all have retained their renal function after a mean follow-up of 6.0 years. However, some patients seem to develop CyA-dependent nephritis.The results were presented as a poster at the 36th meeting of the European Society for Pediatric Nephrology in Bilbao     

Increased frequency of HLA A2/DR4 and A2/DR8 haplotypes in young saskatchewan aboriginal people with diabetic end-stage renal disease

AIMS: To determine the association of HLA with diabetic end-stage renal disease (DESRD) in Saskatchewan aboriginal people. METHODS: This was a retrospective study of HLA profiles in four groups of Saskatchewan residents with ESRD diagnosed from 1980 to 1998: aboriginal people with and without DESRD, and non-aboriginal people with and without DESRD. The aboriginal DESRD group was also subdivided into those 50 years of age. Frequencies of individual and combinations of HLA antigens were compared between groups and subgroups. RESULTS: HLA data were available for 634 subjects. Young aboriginal people with DESRD had a higher frequency of HLA-A2 than older AB DESRD subjects (69 vs. 36%; p = 0.03), and of HLA-DR4 and/or DR8 compared to older AB DESRD subjects (91 vs. 68%; p = 0.07) and AB non-DESRD subjects (91 vs. 67%; p = 0.03). Over 65% of young AB DESRD subjects had either an A2/DR4 or A2/DR8 haplotype (odds ratio 5.09 [confidence intervals 1.35, 20.15] versus older AB DESRD subjects; odds ratio 3.32 [confidence intervals 1.20, 9.3] versus AB non-DESRD subjects). Forty percent of young AB DESRD subjects were homozygous for at least one of A2, DR4 or DR8. CONCLUSIONS: Our findings suggest that DESRD in young AB subjects with T2DM has a genetic basis related to HLA.