Male microbiota-associated metabolite restores macrophage efferocytosis in female lupus-prone mice via activation of PPARγ/LXR signaling pathways.

Systemic lupus erythematosus development is influenced by both sex and the gut microbiota. Metabolite production is a major mechanism by which the gut microbiota influences the immune system, and we have previously found differences in the fecal metabolomic profiles of lupus-prone female and lupus-resistant male BWF1 mice. Here we determine how sex and microbiota metabolite production may interact to affect lupus. Transcriptomic analysis of female and male splenocytes showed genes that promote phagocytosis were upregulated in BWF1 male mice. Because patients with systemic lupus erythematosus exhibit defects in macrophage-mediated phagocytosis of apoptotic cells (efferocytosis), we compared splenic macrophage efferocytosis in vitro between female and male BWF1 mice. Macrophage efferocytosis was deficient in female compared to male BWF1 mice but could be restored by feeding male microbiota. Further transcriptomic analysis of the genes upregulated in male BWF1 mice revealed enrichment of genes stimulated by PPARγ and LXR signaling. Our previous fecal metabolomics analyses identified metabolites in male BWF1 mice that can activate PPARγ and LXR signaling and identified one in particular, phytanic acid, that is a very potent agonist. We show here that treatment of female BWF1 splenic macrophages with phytanic acid restores efferocytic activity via activation of the PPARγ and LXR signaling pathways. Furthermore, we found phytanic acid may restore female BWF1 macrophage efferocytosis through upregulation of the proefferocytic gene CD36. Taken together, our data indicate that metabolites produced by BWF1 male microbiota can enhance macrophage efferocytosis and, through this mechanism, could potentially influence lupus progression.

Using Multiple Analytical Platforms to Investigate the Androgen Depletion Effects on Fecal Metabolites in a Mouse Model of Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by circulating autoantibodies that deposit in target organs (e.g., kidneys), resulting in chronic inflammation and eventual destruction of the organ. SLE is much more prevalent in females than males in both humans and spontaneous mouse models of lupus, such as NZBxNZW F1 (BWF1) mice. Depleting androgens by castration dramatically increases the susceptibility of BWF1 male to lupus. We compared fecal metabolite profiles of castrated BWF1 (androgen-depleted) male, intact (androgen-replete) male, and female mice. Four analytical platforms were employed to study the profiles of polar metabolites in mouse feces collected from adult BWF1 mice, and a total of 435 metabolites was identified. Of these, the abundance levels of 72 metabolites were significantly different between castrated and intact male groups, and 63 metabolites were different between female and male groups. Pathway analysis indicated that the pathway differences between castrated and intact male mice closely resembled the pathway differences between female and intact male mice, suggesting that low levels of androgens, whether due to depletion (castrated male) or endogenous (female), are associated with multiple fecal metabolomic alterations, which could potentially affect SLE progression. Our findings demonstrate that analyzing fecal metabolites using multiple analytical platforms holds great promise for detecting metabolomic alterations in complex disease model systems.

Comparison of cast materials for the treatment of congenital idiopathic clubfoot using the Ponseti method: a prospective randomized controlled trial.

BACKGROUND: The Ponseti method of congenital idiopathic clubfoot correction has traditionally specified plaster of Paris (POP) as the cast material of choice; however, there are negative aspects to using POP. We sought to determine the influence of cast material (POP v. semirigid fibreglass [SRF]) on clubfoot correction using the Ponseti method. METHODS: Patients were randomized to POP or SRF before undergoing the Ponseti method. The primary outcome measure was the number of casts required for clubfoot correction. Secondary outcome measures included the number of casts by severity, ease of cast removal, need for Achilles tenotomy, brace compliance, deformity relapse, need for repeat casting and need for ancillary surgical procedures. RESULTS: We enrolled 30 patients: 12 randomized to POP and 18 to SRF. There was no difference in the number of casts required for clubfoot correction between the groups (p = 0.13). According to parents, removal of POP was more difficult (p < 0.001), more time consuming (p < 0.001) and required more than 1 method (p < 0.001). At a final follow-up of 30.8 months, the mean times to deformity relapse requiring repeat casting, surgery or both were 18.7 and 16.4 months for the SRF and POP groups, respectively. CONCLUSION: There was no significant difference in the number of casts required for correction of clubfoot between the 2 materials, but SRF resulted in a more favourable parental experience, which cannot be ignored as it may have a positive impact on psychological well-being despite the increased cost associated.

CONTEXTE: La méthode de Ponseti pour la correction du pied bot congénital idiopathique a de tout temps spécifié l'utilisation du plâtre de Paris comme matériau de choix; il y a toutefois certains inconvénients associés au plâtre de Paris. Nous avons voulu déterminer l'influence du matériau utilisé (plâtre de Paris c. fibre de verre semi-rigide) sur la correction du pied bot selon la méthode de Ponseti. MÉTHODES: Les patients ont été assignés aléatoirement soit au plâtre de Paris soit à la fibre de verre semi-rigide en vue de l'intervention de Ponseti. Le principal paramètre mesuré était le nombre de plâtres requis pour corriger le pied bot. Les paramètres secondaires incluaient le nombre de plâtres en fonction de la gravité, la facilité de retrait du plâtre, la nécessité de sectionner le tendon d'Achille, le port assidu de l'attelle, le retour de la difformité, la nécessité d'autres plâtres et interventions chirurgicales auxiliaires. RÉSULTATS: Nous avons inscrit 30 patients : 12 ont été assignés au plâtre de Paris et 18 à la fibre de verre. On n'a noté aucune différence entre les groupes quant au nombre de plâtres requis pour la correction du pied bot (p = 0,13). Selon les parents, le retrait du plâtre de Paris était plus difficile p < 0,001), prenait plus de temps (p < 0,001) et nécessitait le recours à plus d'une méthode (p < 0,001). Au moment du dernier suivi à 30,8 mois, les intervalles moyens avant un retour de la difformité nécessitant la pose d'un autre plâtre et/ou une chirurgie ont été de 18,7 et 16,4 mois dans les groupes traités au moyen de la fibre de verre semi-rigide et du plâtre de Paris, respectivement.. CONCLUSION: On n'a noté aucune différence significative entre les 2 matériaux quant au nombre de plâtres requis pour corriger le pied bot, mais la fibre de verre a donné lieu à une expérience plus agréable pour les parents, ce qui ne peut être ignoré en raison de l'impact potentiellement positif sur le bien-être psychologique, et ce, malgré un coût plus élevé.

Computer-aided optimal design of custom scoliosis braces considering clinical and patient evaluations.

Scoliosis causes an abnormal three dimensional curvature of the spine that is often treated by an orthotic device called brace. The objective of this research was to develop a new approach to automatically identify the optimal design of custom-built brace, based on clinical and patient evaluations. In this approach, torso geometry of the scoliosis patient was achieved using a 3-D imaging system that generated a 3-D torso surface model, which was modified using a custom CAD system to design the 3-D brace surface model. Two design parameters, a translational correction factor and a rotational correction factor, were selected to design the brace geometry from the torso geometry. The 3-D digital brace was evaluated by three clinical evaluation measures (imbalance, rib hump and principal axis angle reduction) and one patient evaluation measure (discomfort). A multi-objective optimization method was employed to identify the optimal design parameters considering both clinical and patient evaluations.

Deep wound infection following pediatric scoliosis surgery: incidence and analysis of risk factors.

BACKGROUND: Deep wound infection after spinal surgery is a severe complication that often requires prolonged medical and surgical management. It can compromise the outcome of the deformity correction, especially in patients requiring surgical intervention with subsequent removal of implants. Ascertaining the incidence and risk factors leading to infection may help to prevent this problem. METHODS: We reviewed the hospital charts of all patients who underwent spinal deformity correction from 1996 to 2005. RESULTS: In all, 227 patients were identified (139 idiopathic, 57 neuromuscular, 8 syndromic, 6 congenital, 17 other); 191 patients were treated with posterior instrumentation and fusion, 11 with anterior-only procedures and 24 with combined anterior and posterior procedures. Final follow-up ranged from 1 to 9.5 years. Infection developed in 14 patients. The overall incidence of infection was 6.2%. Drainage and back pain were the most common presenting symptoms. The incidence of infection was higher among patients with nonidiopathic diagnoses (risk ratio [RR] 8.65, p < 0.001). Use of allograft bone was associated with a higher rate of infection (RR 9.66, p < 0.001) even when stratified by diagnosis (nonidiopathic diagnoses, RR 7.6, p = 0.012). Higher volume of instrumentation was also a risk factor for infection (p = 0.022). Coagulase-negative Staphyloccocus was the most commonly identified organism, followed by Propionibacterium acnes and Pseudomonas. CONCLUSION: Development of infection following scoliosis surgery was found to be associated with several risk factors, including a nonidiopathic diagnosis, the use of allograft and a higher volume of instrumentation. Preventative measures addressing these factors may decrease the rate of infection.

Time series spinal radiographs as prognostic factors for scoliosis and progression of spinal deformities.

The effectiveness of clinical measures to predict scoliotic progression is unclear. The objective of this study was to identify potential prognostic factors affecting scoliosis progression. Consecutive measurements (181) from 35 non-instrumented adolescent idiopathic scoliosis patients with at least two follow-up assessments were studied. Potential prognostic factors of gender, curve pattern, age, curve magnitude, apex location and lateral deviation and spinal growth were analyzed. Stable and progressed groups were compared (threshold: Cobb angle ≥5° or 10°) with sequential clinical data collected in 6-month intervals. Double curves progressed simultaneously or alternatively on curve regions. Age was not significantly different prior to and at maximal Cobb angle. Maximal Cobb angles were significantly correlated to initial Cobb angles (r = 0.81-0.98). Progressed males had larger initial Cobb angles than progressed females. Apex locations were higher in progressed than stable groups, and at least a half vertebra level higher in females than males. Maximal apex lateral deviations correlated significantly with the initial ones (r = 0.73-0.97) and moderately with maximal Cobb angles (r = 0.33-0.85). In the progressed groups, males had larger apex lateral deviations than females. Spinal growth did not relate to curve progression (r = -0.64 to +0.59) and was not significantly different between groups and genders. Scoliosis may dynamically progress between major and minor curves. Gender, curve magnitude, apex location and lateral deviation have stronger effects on scoliosis progression than age or spinal growth. Females with high apex locations may be expected to progress.

Prediction of scoliosis progression with serial three-dimensional spinal curves and the artificial progression surface technique.

Adolescent idiopathic scoliosis (AIS) progression is clinically monitored by a series of full spinal X-rays. To decrease radiation exposure, an artificial progression surface (APS) is proposed to predict progression. Fifty-six acquisitions (posteroanterior radiographs, 0° and 20°) were obtained from 11 AIS patients (29.8 ± 9.6° Cobb angle). Three-dimensional curves were constructed through vertebral pedicle centers. Three previous serial spinal curves (6-month intervals) were used to construct an APS with a Non-uniform Rational B-Spline surfacing technique. Future progression was achieved by aligning the curves on the APS using the generalized cross-validation extrapolation technique. With three and four previous serial spinal curves, the prediction accuracies of future progression at the next 6-month interval were 4.1 ± 3.3° for Cobb angles and 3.6 ± 3.5 mm for apex lateral deviations. Apex locations and Cobb regions varied within one vertebral level. The proposed technique shows potential as an accurate three-dimensional prediction method for AIS progression and could help pediatricians make decisions about treatment. However, it could only be applied once before more radiographic data would be needed.

Perioperative blood transfusion requirements in pediatric scoliosis surgery: the efficacy of tranexamic acid.

BACKGROUND: Previous studies have noted that the use of antifibrinolytic medications can help reduce blood loss and transfusion requirements during cardiac, total joint arthroplasty, and spine surgery. Tranexamic acid (TXA) has been investigated in these patient groups but consensus with respect to the dosing regimen has not been achieved, especially in the pediatric scoliosis literature. The purpose of this study was to compare the effects of 2 TXA dosing regimens on reducing transfusion requirements. METHODS: A retrospective chart review was performed on all idiopathic scoliosis patients undergoing posterior spinal instrumentation and fusion from 2005 to 2006 to determine total perioperative transfusion requirements. Transfusion requirements for those patients receiving either a low (10 mg/kg loading, 1 mg/kg/h infusion) or high (20 mg/kg loading, 10 mg/kg/h infusion) dose of TXA were compared. RESULTS: High-dose TXA (n = 11) showed a trend toward a reduction in transfusion requirements compared with the low dose (n = 15) for idiopathic scoliosis patients undergoing posterior only instrumentation and fusion (687.9 +/- 778.1 mL vs 1372.6 +/- 1077.3 mL; P = 0.07; 95% confidence interval for the mean difference, -66.3 mL to 1435.7 mL). Although substantial, this difference was underpowered to show a difference. CONCLUSIONS: The use of the higher dose of TXA resulted in a 50% reduction in transfusion requirements for idiopathic scoliosis patients. Given previous studies, there appears to be a dose-response effect. A prospective dose-ranging study is now required to determine the optimal dose for pediatric patients with idiopathic scoliosis. LEVEL OF EVIDENCE: III, retrospective cohort study.

Bronchial obstruction secondary to idiopathic scoliosis in a child: a case report.

INTRODUCTION: Patients with severe idiopathic scoliosis are reported to have significant pulmonary complications, including recurrent chest infections, alveolar hypoventilation and respiratory failure. CASE PRESENTATION: We report a case of a 13-year-old boy with moderate-to-severe scoliosis resulting in torsion or twisting of the bronchus intermedius, which contributed to airflow obstruction defects, as revealed by both spirometry and bronchoscopy. CONCLUSION: We recommend that inspection of the shape of the maximal expiratory flow-volume loop obtained from spirometry, as well as other parameters suggestive of obstructive lung disease, may be important in children with scoliosis. To the best of the authors' knowledge, this is the first report of a child in which pulmonary function testing and direct visualization via a flexible bronchoscope have been used to characterize intrathoracic large airway obstruction.

Femoral fractures in children younger than three years: the role of nonaccidental injury.

BACKGROUND: Nonaccidental injury (NAI) in children is a major cause of morbidity and mortality, with fractures being the second most common presentation. The presence of a femur fracture has been reported to be suggestive of nonaccidental trauma in 30% to 60% of young children. The purpose of this study was to determine the percentage of NAI in children younger than 3 years presenting with a femur fracture to a single institution within a western Canadian population. METHODS: A retrospective cohort study was performed for children younger than 3 years who presented to the Alberta Children's Hospital during the years 1994 to 2005. The primary outcome variable was the percentage of NAI associated with femur fracture. Secondary outcome variables included patient demographics, injury characteristics, radiological and other workup, and suspicion of NAI. RESULTS: The overall percentage of NAI was 11% (14/127 patients) and 17% (10/60 patients) in children younger than 12 months. Age younger than 12 months (P = 0.04), nonambulatory status (P = 0.004), delayed presentation (P = 0.002), mechanism of injury unwitnessed or inconsistent (P = 0.008), and other associated injuries (P = 0.006) were significant risk factors for NAI. CONCLUSIONS: Children younger than 3 years who present with femoral fracture are at risk for associated NAI, although perhaps this risk is not as high as previously thought. Regardless, a high index of suspicion is mandatory when these children are encountered, and careful screening with a thorough history, physical examination, and other investigations, where indicated, is warranted to rule out associated NAI. LEVEL OF EVIDENCE: Retrospective cohort study, level IV.

Scoliotic progression patterns in prognostic factors and future prediction of spinal deformity progression.

This study investigated how an adolescent idiopathic scoliosis progresses with time. 154 consecutive measurements from 26 consecutive AIS patients were analyzed. Each subject had at least four successive scans at six-month intervals. Progression patterns of Cobb angle and apex lateral deviation were extracted from 34 serial data sets of the most common AIS type RT-LL, in the format of four serial data sets, by using the fuzzy c-means clustering technique. Progression of spinal deformity was predicted with previous serial data of Cobb angle and apex lateral deviation by using a GCV extrapolating technique alone and in conjunction with progression patterns. Our results showed that scoliotic progression appears to follow progression patterns. Progression of spinal deformity has potential to be accurately predicted with previous serial spinal deformities by using GCV extrapolating technique with assistance of progression patterns.

The Calgary protocol for bracing of pectus carinatum: a preliminary report.

BACKGROUND: The optimal treatment of pectus carinatum (PC) deformities is unclear. We propose a nonoperative approach using a lightweight, patient-controlled dynamic chest-bracing device. MATERIAL AND METHODS: With ethical approval, 24 patients with PC were treated at the Alberta Children's Hospital between January 1998 and April 2005. There were 6 (25%) females and 18 (75%) males, with a mean age of 12.9 years at the onset of treatment. Treatment involved fitting of a lightweight, patient-controlled chest brace, worn for 23 hours per day (correction phase [CP]) until the convex deformity was corrected. Following correction of the deformity, bracing was reduced to 8 hours per day (maintenance phase) until axial skeletal maturation ceased. Monitoring was done by measurement of the external pectus carinatum protrusion as well as subjective patient and surgeon appraisal of appearance and exercise tolerance. RESULTS: Nineteen (79.2%) patients have completed initial treatment (mean CP time, 4.3 +/- 2.1 months). There were 3 patients (12.5%) who were noncompliant, and 2 (8.3%) are still in the initial CP phase of therapy. Fourteen (58.3%) patients are presently in maintenance phase, nocturnally braced, and 2 (8.3%) have completed therapy. In patients completing initial treatment, the protrusion pectus carinatum protrusion (pre 22 +/- 6 vs post 6.0 +/- 6.2) and subjective appearance (change + 1.8+/-0.4) showed a significant improvement (P < .001 for both) with no change in exercise tolerance. CONCLUSION: Compressive bracing results in a significant subjective and objective improvement in PC appearance in skeletally immature patients. However, patient compliance and diligent follow up appear to be paramount for the success of this method of treatment. Further studies are required to show the durability of this method of treatment.

Prediction of scoliosis progression in time series using a hybrid learning technique.

Scoliosis is a common and poorly understood spinal disorder that is clinically monitored with a series of full spinal X-rays. The purpose of this study was to predict scoliosis future progression at 6- and 12-month intervals with successive spinal indices and a hybrid learning technique (i.e., the combination of fuzzy c-means clustering and artificial neural network (ANN)). Ultimately this could decrease scoliotic patients' radiation exposure and the associated cancer risk in growing adolescents. Seventy-two data sets were derived from a database of 56 acquisitions from 11 subjects (29.8 +/- 9.6 degrees Cobb angle, 11.4 +/- 2.4 yr), each consisting of 4 sequential values of Cobb angle and lateral deviations at apices in 6- and 12-month intervals in the coronal plane. Progression patterns in Cobb angles (n = 10) and lateral deviations (n = 8) were successfully identified using a fuzzy c-means clustering algorithm. The accuracies of the trained ANN, having a structure of three input variables, four nonlinear hidden nodes, and one linear output variable, for training and test data sets were within 3.64 degrees (+/- 2.58 degrees) and 4.40 degrees (+/- 1.86 degrees) of Cobb angles, and within 3.59 (+/-3.96) mm and 3.98 (+/- 3.41) mm of lateral deviations, respectively. Those results were twice the accuracy of typical clinical measurement (~10 degrees) and in close agreement with those using cubic spline extrapolation and adaptive neuro-fuzzy inference system (ANFIS) techniques. The adapted technique for predicting the scoliosis deformity progression holds significant promise for clinical applications.

Genetic algorithm-neural network estimation of cobb angle from torso asymmetry in scoliosis.

Scoliosis severity, measured by the Cobb angle, was estimated by artificial neural network from indices of torso surface asymmetry using a genetic algorithm to select the optimal set of input torso indices. Estimates of the Cobb angle were accurate within 5 degrees in two-thirds, and within 10 degrees in six-sevenths, of a test set of 115 scans of 48 scoliosis patients, showing promise for future longitudinal studies to detect scoliosis progression without use of X-rays.

Indices of torso asymmetry related to spinal deformity in scoliosis.

OBJECTIVE: To develop indices that quantify 360 degrees torso surface asymmetry sufficiently well to estimate the Cobb angle of scoliotic spinal deformity within the clinically important 5-10 degrees range. DESIGN: Prospective study in 48 consecutive adolescent scoliosis patients (Cobb angles 10-71 degrees ). BACKGROUND: Scoliotic surface asymmetry has been quantified on the back surface by indices such as back surface rotation (BSR) and curvature of the spinous process line and torso centroid line, though with limited success in spinal deformity estimation. Quantification of 360 degrees torso shape may enhance surface-spine correlation and permit reduced use of harmful X-rays in scoliosis. METHODS: For each patient a 3D torso surface model was generated concurrently with postero-anterior X-rays. We computed indices describing principal axis orientation, back surface rotation, and asymmetry of the torso centroid line, left and right half-areas and the spinous process line. We calculated correlations of each index to the Cobb angle and used stepwise regression to estimate the Cobb angle. RESULTS: Several torso asymmetry indices correlated well to the Cobb angle (r up to 0.8). The Cobb angle was best estimated by age, rib hump and left-right variation in torso width in unbraced patients and by centroid lateral deviation in braced patients. A regression model estimated the Cobb angle from torso indices within 5 degrees in 65% of patients and 10 degrees in 88% (r=0.91, standard error=6.1 degrees ). CONCLUSION: Consideration of 360 degrees torso surface data yielded indices that correlated well to the Cobb angle and estimated the Cobb angle within 10 degrees in 88% of cases. RELEVANCE: The torso asymmetry indices developed here show a strong surface-spine relation in scoliosis, encouraging development of a model to detect scoliosis magnitude and progression from the surface shape with minimal X-ray radiation.

Comparison of Cobb angles measured manually, calculated from 3-D spinal reconstruction, and estimated from torso asymmetry.

While scoliotic spinal deformity is traditionally measured by the Cobb angle, we seek to estimate scoliosis severity from the torso surface without X-ray radiation. Here, we measured the Cobb angle in three ways: by protractor from postero-anterior X-ray, by computer from a 3-D digitized model of the vertebral body line, and by neural-network estimation from indices of torso surface asymmetry. The estimates of the Cobb angle by computer and by neural network were equally accurate in 153 records from 52 patients (standard deviation of 6 degrees from the Cobb angle, r=0.93), showing that torso asymmetry reliably predicted spinal deformity. Further improvements in predictive accuracy may require estimation of other 3-D indices of spinal deformity besides the Cobb angle with its wide measurement variability.

Prediction of spinal deformity in scoliosis from geometric torsion.

The shape of a curved line that passes through thoracic and lumbar vertebrae is often used to study spinal deformity with measurements in "auxiliary" planes that are not truly three-dimensional (3D). Here we propose a new index, the geometric torsion, which could uniquely describe the spinal deformity. In this study we assessed whether geometric torsion could be effectively used. to predict spinal deformity with the aid of multiple linear regression. Anatomical landmarks were obtained from multi-view radiographic reconstruction and used to generate 3D model of the spine and rib cage of 28 patients. Fourier series best fitted to the vertebral centroids approximated the spinal shape. For each patient, spinal deformity indices were computed. Torsion was calculated and 20 derived parameters were recorded. Torsion inputs were used in a multiple linear regression model for prediction of key spinal indices. The primary clinical Cobb angle (mainly thoracic) was predicted well, with r=0.89 using all 20 inputs of torsion or r=0.83 using just two. Torsion was also well related to the orientation of plane of maximal deformity (r=0.87). Torsion was less accurate but still significant in predicting maximal vertebral axial rotation (r=0.77). This preliminary study showed promising results for the use of geometric torsion as an alternative 3D index of spinal deformity.