1,25‐Dihydroxyvitamin D Alone Improves Skeletal Growth,Microarchitecture, and Strength in a Murine Model of XLH,Despite Enhanced FGF23 Expression

X‐linked hypophosphatemia (XLH) is characterized by impaired renal tubular reabsorption of phosphate owing to increased circulating FGF23 levels, resulting in rickets in growing children and impaired bone mineralization. Increased FGF23 decreases renal brush border membrane sodium‐dependent phosphate transporter IIa (Npt2a) causing renal phosphate wasting, impairs 1‐α hydroxylation of 25‐hydroxyvitamin D, and induces the vitamin D 24‐hydroxylase, leading to inappropriately low circulating levels of 1,25‐dihydroxyvitamin D (1,25D). The goal of therapy is prevention of rickets and improvement of growth in children by phosphate and 1,25D supplementation. However, this therapy is often complicated by hypercalcemia and nephrocalcinosis and does not always prevent hyperparathyroidism. To determine if 1,25D or blocking FGF23 action can improve the skeletal phenotype without phosphate supplementation, mice with XLH (Hyp) were treated with daily 1,25D repletion, FGF23 antibodies (FGF23Ab), or biweekly high‐dose 1,25D from d2 to d75 without supplemental phosphate. All treatments maintained normocalcemia, increased serum phosphate, and normalized parathyroid hormone levels. They also prevented the loss of Npt2a, α‐Klotho, and pERK1/2 immunoreactivity observed in the kidneys of untreated Hyp mice. Daily treatment with 1,25D decreased urine phosphate losses despite a marked increase in bone FGF23 mRNA and in circulating FGF23 levels. Daily 1,25D was more effective than other treatments in normalizing the growth plate and metaphyseal organization. In addition to being the only therapy that normalized lumbar vertebral height and body weight, daily 1,25D therapy normalized bone geometry and was more effective than FGF23Ab in improving trabecular bone structure. Daily 1,25D and FGF23Ab improved cortical microarchitecture and whole‐bone biomechanical properties more so than biweekly 1,25D. Thus, monotherapy with 1,25D improves growth, skeletal microarchitecture, and bone strength in the absence of phosphate supplementation despite enhancing FGF23 expression, demonstrating that 1,25D has direct beneficial effects on the skeleton in XLH, independent of its role in phosphate homeostasis. © 2016 American Society for Bone and Mineral Research.     

Serial elongation,derotation and flexion (EDF) casting under general anesthesia and neuromuscular blocking drugs improve outcome in patients with juvenile scoliosis: preliminary results

Purpose

Juvenile scoliosis (JS), among different types of spinal deformity, remains still a challenge for orthopedic surgeons. Elongation, derotation and flexion (EDF) casting technique is a custom-made thoracolumbar cast based on a three-dimensional correction concept. The primary objective of the present study was to measure changes on plain radiographs of patients with JS treated with EDF plaster technique. The second aim was to evaluate the effectiveness of the EDF plaster technique realized under general anesthesia (GA) and neuromuscular blocking drugs, i.e. curare, on the radiological curve correction.

Methods

A retrospective comparative case series study was performed in which were included forty-four skeletally immature patients. Three patient groups were selected. Group 1: EDF cast applied with patients awaken and no anesthesia; Group 2: EDF cast applied under GA without neuromuscular blocking drugs; Group 3: EDF cast applied under GA with neuromuscular blocking drugs. All the patients were treated with two serial EDF casts by 2 months and a half each. All measurements were taken from the radiographic exams. Cobb’s angle; RVAD and Nash and Moe grade of rotation were assessed before and after applying the cast. Thirty-four (77.3 %) patients were followed up at least 24 months after removal of last EDF cast.

Results

Eighteen patients (3 males, 15 females) were included in Group 1, 12 (2 males, 10 females) in Group 2 and 14 (5 males, 9 females) in Group 3. Serial EDF casting was more effective at initial curve reduction and in preventing curve progression when applied under GA with neuromuscular blocking drugs, i.e. curare. RVAD and Nash and Moe score improved significantly in all groups of patients treated according to principles of EDF technique. During follow-up period, six patients required surgery in Group 1 (6/18; 33.3 %), 3 patients required surgery in Group 2 (3/12; 25 %) and 2 patients underwent surgery in Group 3 (2/14; 15 %).

Conclusions

Preliminary results show EDF casting is effective in controlling the curve in both frontal (Cobb’s angle) and transverse plane (rib vertebral angle and apical vertebral rotation degree).

     

Increased Act1/IL-17R expression in Hirschsprung’s disease

Purpose

Hirschsprung’s disease-associated enterocolitis (HAEC) is the most common cause of morbidity and mortality in Hirschsprung’s disease (HSCR). Altered intestinal epithelial barrier function is implicated in the pathogenesis of HAEC. IL-17 is a proinflammatory cytokine that plays a crucial role in host defense against microbial organisms in the development of inflammatory diseases. Act1 is an essential adaptor molecule required for the IL-17-mediated inflammatory responses via interaction with IL-17 receptor (IL-17R). We designed this study to investigate the hypothesis that Act1/Il-17R expression is upregulated in HSCR.

Methods

We investigated Act1 and IL17R expression in ganglionic andaganglionic bowel of HD patients (n = 10) and controls (n = 10). qPCR, Western blotting and confocal immunofluorescence were performed.

Main results

qPCR and Western blot analysis revealed that Act1 and IL17R are strongly expressed in the aganglionic and ganglionic colon of patients with HSCR. Act1 and IL17R expression was significantly increased in HSCR specimens compared to controls (p < 0.05). Confocal microscopy revealed a markedly increased expression of Act1 and IL17R in the colonic epithelium of patients with HSCR compared to controls.

Conclusion

To our knowledge, we report, for the first time, the expression of Act1 in the human colon. The increased expression of Act1 and Il-17 in the aganglionic and ganglionic bowel in HSCR may result in IL-17-mediated increased inflammatory response leading to the development of HAEC

     

Identifying predictors of resilience at inpatient and 3-month post-spinal cord injury

Objectives

To identify (1) changes in psychosocial factors, (2) relationships between psychosocial factors, and (3) significant predictors of resilience in adults with spinal cord injury (SCI) during inpatient rehabilitation and at 3-month post-discharge.

Design

Cross sectional with convenience sample based on inclusion/exclusion criteria.

Setting

Inpatient rehabilitation hospital and community-based follow-up.

Participants

Individuals with a SCI.

Interventions

Not applicable.

Outcome measures

Demographic, resilience, self-efficacy for managing a chronic health issue, depression, social roles/activity limitations, and pain.

Results

The final sample consisted of 44 respondents (16 women and 28 men). Results of repeated measure analyses of variance indicated no significant changes in variables between inpatient and 3-month follow-up. Bivariate correlations revealed associations between resilience and self-efficacy at inpatient (r = 0.54, P < 0.001), and resilience and depression (r = −0.69, P < 0.001) and self-efficacy (r = 0.67, P < 0.001) at 3-month follow-up. Hierarchical regression analyses a significant model predicting resilience at inpatient stay (R = 0.61; adjusted R² = 0.24, P = 0.023), and at 3-month follow-up (R = 0.83; adjusted R² = 0.49, P = 0.022). Self-efficacy was the strongest predictor at inpatient stay (β = 0.46, P  =  0.006) and depression was strongest at 3-month follow-up (β = −0.80, P = 0.007).

Conclusion

Results suggest that although resilience appears to be stable from inpatient to 3-month follow-up, different factors are stronger predictors of resilience across time. Based on current results, an assessment of self-efficacy during inpatient rehabilitation and an identification of depression at 3-month follow-up may be important factors to help identify those at risk of health issues overtime.     

Maximizing Weight Loss After Roux-en-Y Gastric Bypass May Decrease Risk of Incident Organ Cancer

Background

Recent studies have suggested that metabolic surgery reduces cancer risk. This study aims to determine if incident cancer is associated with the extent of weight loss after Roux-en-Y gastric bypass (RYGB).

Methods

Patients at a large tertiary bariatric surgery center were retrospectively reviewed to identify patients with no history of cancer at the time of RYGB. Diagnoses in the electronic health record, a tumor registry, and chart review were used to identify postoperative incident solid organ cancer. The overall incidence of organ cancer was estimated using Kaplan-Meier analysis. The percent total body weight loss (%TWL) in the 48 months after surgery but prior to cancer was compared between those that developed organ cancer versus those that did not using repeated measures linear regression.

Results

The 2943 patients had a mean age of 45.6 years (SD?=?11.1), 81 % were female, and a mean baseline body mass index (BMI) of 47.2 kg/m² (SD?=?7.9). Median follow-up after surgery was 3.8 years (range?=?[<1, 12]). Incident organ cancer developed and was verified in 54 of the 2943 patients (1.8 %). Kaplan-Meier estimates for cancer at 3, 5, and 10 years postsurgery were 1.3, 2.5, and 4.2 %. After adjusting for age, BMI, sex, diabetes, hypertension, and dyslipidemia, patients that developed organ cancer achieved less weight loss (?1.5 % TWL, 95 % CI?=?[?2.9 %, ?0.1 %], p?=?0.034).

Conclusions

Greater weight loss after metabolic surgery may be associated with lower organ cancer risk.