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Adolescent idiopathic scoliosis (AIS) is a common and progressive spinal deformity in children that exhibits striking sexual dimorphism, with girls at more than five-fold greater risk of severe disease compared to boys. Despite its medical impact, the molecular mechanisms that drive AIS are largely unknown. We previously defined a female-specific AIS genetic risk locus in an enhancer near thePAX1gene. Here we sought to define the roles ofPAX1and newly-identified AIS-associated genes in the developmental mechanism of AIS. In a genetic study of 9,161 individuals with AIS and 80,731 unaffected controls, significant association was identified with a variant inCOL11A1encoding collagen (α1) XI (rs3753841; NM_080629_c.4004C>T; p.(Pro1335Leu); P=7.07e−11, OR=1.118). Using CRISPR mutagenesis we generatedPax1knockout mice (Pax1−/−). In postnatal spines we found that Pax1 and collagen (α1) XI protein both localize within the intervertebral disc (IVD)-vertebral junction region encompassing the growth plate, with less collagen (α1) XI detected inPax1−/−spines compared to wildtype. By genetic targeting we found that wildtypeCol11a1expression in growth plate cells (GPCs) suppresses expression ofPax1and ofMmp3, encoding the matrix metalloproteinase 3 enzyme implicated in matrix remodeling. However, this suppression was abrogated in the presence of the AIS-associatedCOL11A1P1335Lmutant. Further, we found that either knockdown of the estrogen receptor geneEsr2, or tamoxifen treatment, significantly alteredCol11a1andMmp3expression in GPCs. These studies support a new molecular model of AIS pathogenesis wherein genetic variation and estrogen signaling increase disease susceptibility by altering aPax1-Col11a1-Mmp3signaling axis in the growth plate.

The purpose of this study was to investigate whether presence of an infolded limbus on hip arthrogram at index closed reduction was associated with increased residual dysplasia or secondary surgery.We retrospectively reviewed all patients who underwent closed reduction for dysplasia of the hip with a minimum 2-year follow-up between 1980 and 2016. Demographic data was obtained including the age at reduction and severity of dislocation based on the International Hip Dysplasia Institute (IHDI) classification. Arthrograms performed at time of closed reduction were separately reviewed by 3 fellowship-trained pediatric orthopaedic surgeons to evaluate for an infolded limbus. The primary radiographic outcome was acetabular indices at 2 and 4 years postreduction. We also assessed the presence of avascular necrosis and rate of secondary reconstructive surgery for residual dysplasia.A total of 182 hips in 165 patients underwent closed reduction at a mean age of 9.8±4.5 mo and were followed a mean of 9.0±4.9 y. An infolded limbus was identified in 20.3% (37/182) hips with substantial agreement among the 3 graders (Fleiss κ=0.75). The frequency of labral infolding increased with the severity of dislocation (8.8%% of IHDI II, 26.7% IHDI III, and 25.0% of IHDI IV hips; P=0.03). Hips with infolded limbus were older at reduction (12.4±5.3 vs. 9.2±5.8 mo, P=0.001). The mean acetabular index was higher in hips with infolded limbus than hips without at 2 years postreduction (34.8±4.8 vs. 32.6±5.8 degrees, respectively; P=0.04). However, multivariate analysis revealed that only the severity of dislocation predicted dysplasia at 2 years postreduction. No significant difference in acetabular index was seen at 4 years postreduction (27.2±7.4 vs. 25.4±6.5 degrees, P=0.24). There was no difference in avascular necrosis between groups (P=0.74). There was no difference in rate of secondary surgery between hips with labral infolding and those without (35% vs. 30%, respectively; P=0.52).An infolded limbus was more common in older patients with more severe dislocations. However, it is not associated with increased residual dysplasia or secondary surgery and may have limited utility in decision-making during closed reduction.Level II-prognostic study.

Introduction Physicians and surgeons in all specialties encounter and manage complications throughout their careers. Little attention has been given to a surgeon's emotional experience and reaction to the stresses of managing complications. Methods The author has reviewed relevant literature and added observations from 4 decades of experience with a pediatric orthopedic faculty. The author also reviewed the types of complications and principles of successful management of surgical complications. Results and discussion A small number of published articles dealing with the issues of physician and surgeon responses to stressful occurrences were found. Proper management of complications will markedly reduce the stress upon the surgeon. Analysis of the complications with colleagues is essential to the reduction of feelings of guilt, and are useful in preventing future events. Discussions of the accompanying stress between the surgeon and colleagues, family, and occasionally counselors are helpful in achieving resolution and emotional healing. Conclusions Greater attention to emotional stress issues affecting caregivers, and especially surgeons, is needed. This should happen at all levels of education from medical school through postgraduate training, and in the everyday practice of surgery. Research to clarify the effectiveness of various interventions is needed.

Most surgical patients receiving regional or general anesthesia experience perioperative hypothermia unless effective preventive measures are used. Patient positioning poses a challenge for clinicians using existing technology. The purpose of this study is to describe outcomes of hypothermia after a combination of preoperative and intraoperative conductive skin warming (CSW). This retrospective observational study included 972 adult surgical patients receiving general or neuraxial anesthesia. Clinicians were provided an alternative for perioperative warming, an underbody conductive warming mattress using resistive ink technology (VitaHEAT UB3, VitaHEAT Medical), or the option to use current practice, forced air warming (FAW). The primary study endpoint was temperature on arrival in the postanesthesia care unit. Active warming was provided preoperatively with CSW (81.5%) or FAW (0.6%) and intraoperatively with CSW (61.1%), FAW (21.8%), or both (12.1%). Hypothermia occurred in 3.5% of patients overall and in 16.7% of patients when active warming was not used. When CSW was used preoperatively and intraoperatively, 4.1% of patients became hypothermic. When CSW was used preoperatively and FAW was used intraoperatively, 2.3% of patients became hypothermic. When clinicians used active warming methods based on individual patient needs, nearly all patients (96.5%) remained normothermic.

Adolescent idiopathic scoliosis (AIS) is the most common musculoskeletal disorder of childhood development. The genetic architecture of AIS is complex, and the great majority of risk factors are undiscovered. To identify new AIS susceptibility loci, we conducted the first genome-wide meta-analysis of AIS genome-wide association studies, including 7956 cases and 88459 controls from 3 ancestral groups. Three novel loci that surpassed genome-wide significance were uncovered in intragenic regions of the CDH13 (P-value_rs4513093=1.7E-15), ABO (P-value_ rs687621=7.3E-10) and SOX6 (P-value_rs1455114=2.98E-08) genes. Restricting the analysis to females improved the associations at multiple loci, most notably with variants within CDH13 despite the reduction in sample size. Genome-wide gene-functional enrichment analysis identified significant perturbation of pathways involving cartilage and connective tissue development. Expression of both SOX6 and CDH13 was detected in cartilage chondrocytes and chromatin immunoprecipitation sequencing experiments in that tissue revealed multiple HeK27ac-positive peaks overlapping associated loci. Our results further define the genetic architecture of AIS and highlight the importance of vertebral cartilage development in its pathogenesis.

Adolescent idiopathic scoliosis (AIS) is a common spinal deformity with the prevalence of approximately 3%. We previously conducted a genome-wide association study (GWAS) using a Japanese cohort and identified a novel locus on chromosome 9p22.2. However, a replication study using multi-population cohorts has not been conducted. To confirm the association of 9p22.2 locus with AIS in multi-ethnic populations, we conducted international meta-analysis using eight cohorts. In total, we analyzed 8,756 cases and 27,822 controls. The analysis showed a convincing evidence of association between rs3904778 and AIS. Seven out of eight cohorts had significant P value, and remaining one cohort also had the same trend as the seven. The combined P was 3.28 × 10−18 (odds ratio = 1.19, 95% confidence interval = 1.14–1.24). In silico analyses suggested that BNC2 is the AIS susceptibility gene in this locus.

Background: The absence of a reliable classification system for Legg-Calve-Perthes disease has contributed to difficulty in establishing consistent management strategies and in interpreting outcome studies. The purpose of this study was to assess interobserver and intraobserver reliability of the modified Waldenstrom classification system among a large and diverse group of pediatric orthopaedic surgeons. Methods: Twenty surgeons independently completed the first two rounds of staging: two assessments of forty deidentified radiographs of patients with Legg-Calve-Perthes disease in various stages. Ten of the twenty surgeons completed another two rounds of staging after the addition of a second pair of radiographs in sequence. Kappa values were calculated within and between each of the rounds. Results: Interobserver kappa values for the classification for surveys 1, 2, 3, and 4 were 0.81, 0.82, 0.76, and 0.80, respectively (with 0.61 to 0.80 considered substantial agreement and 0.81 to 1.0, nearly perfect agreement). Intraobserver agreement for the classification was an average of 0.88 (range, 0.77 to 0.96) between surveys 1 and 2 and an average of 0.87 (range, 0.81 to 0.94) between surveys 3 and 4. Conclusions: The modified Waldenstrom classification system for staging of Legg-Calve-Perthes disease demonstrated substantial to almost perfect agreement between and within observers across multiple rounds of study. In doing so, the results of this study provide a foundation for future validation studies, in which the classification stage will be associated with clinical outcomes.

Adolescent idiopathic scoliosis (AIS) is the most common pediatric skeletal disease. We previously reported a locus on chromosome 10q24.31 associated with AIS susceptibility in Japanese using a genome-wide association study (GWAS) consisting of 1,033 cases and 1,473 controls. To identify additional AIS-associated loci, we expanded the study by adding X-chromosome SNPs in the GWAS and increasing the size of the replication cohorts. Through a stepwise association study including 1,819 cases and 25,939 controls, we identified a new susceptibility locus on chromosome 6q24.1 in Japanese (P = 2.25 × 10(-10); odds ratio (OR) = 1.28). The most significantly associated SNP, rs6570507, was in GPR126 (encoding G protein-coupled receptor 126). Its association was replicated in Han Chinese and European-ancestry populations (combined P = 1.27 × 10(-14); OR = 1.27). GPR126 was highly expressed in cartilage, and the knockdown of gpr126 in zebrafish caused delayed ossification of the developing spine. Our results should provide insights into the etiology and pathogenesis of AIS.

Elective amputation has an important role in the management of children with limb deficiencies. Social awareness and acceptance of people with prosthetic limbs has come about in concert with highly functional prostheses, outstanding athletic performance, Paralympic games, and mainstreaming of school children. Parents must become fully aware of the advantages and disadvantages of reconstructive options for their child in order to select the treatment which best fits the needs of their child and their family. This chapter reviews the role of amputation in the management of congenital lower limb deficiencies as well as those related to trauma, tumor, and other syndromes.

Adolescent idiopathic scoliosis (AIS) is an unexplained and common spinal deformity seen in otherwise healthy children. Its pathophysiology is poorly understood despite intensive investigation. Although genetic underpinnings are clear, replicated susceptibility loci that could provide insight into etiology have not been forthcoming. To address these issues, we performed genome-wide association studies (GWAS) of ∼327 000 single nucleotide polymorphisms (SNPs) in 419 AIS families. We found strongest evidence of association with chromosome 3p26.3 SNPs in the proximity of the CHL1 gene (P < 8 × 10(-8) for rs1400180). We genotyped additional chromosome 3p26.3 SNPs and tested replication in two follow-up case-control cohorts, obtaining strongest results when all three cohorts were combined (rs10510181 odds ratio = 1.49, 95% confidence interval = 1.29-1.73, P = 2.58 × 10(-8)), but these were not confirmed in a separate GWAS. CHL1 is of interest, as it encodes an axon guidance protein related to Robo3. Mutations in the Robo3 protein cause horizontal gaze palsy with progressive scoliosis (HGPPS), a rare disease marked by severe scoliosis. Other top associations in our GWAS were with SNPs in the DSCAM gene encoding an axon guidance protein in the same structural class with Chl1 and Robo3. We additionally found AIS associations with loci in CNTNAP2, supporting a previous study linking this gene with AIS. Cntnap2 is also of functional interest, as it interacts directly with L1 and Robo class proteins and participates in axon pathfinding. Our results suggest the relevance of axon guidance pathways in AIS susceptibility, although these findings require further study, particularly given the apparent genetic heterogeneity in this disease.

Osteochondritis dissecans is a pathologic fragmentation of a segment of subchondral bone and its overlying cartilage. Although the exact etiology is unclear, one commonly accepted theory is a focal interruption in blood supply to the periarticular bone1. Osteochondritis dissecans lesions are most commonly seen in the distal part of the femur, the distal part of the humerus, and the talus. Involvement of the femoral head is rare and typically is associated with skeletal dysplasias or Legg-Calve-Perthes disease. Idiopathic osteochondritis dissecans of the femoral head is extremely rare and is typically unilateral2. We present three cases of bilateral idiopathic femoral head osteochondritis dissecans that occurred in multiple members of the same family over three generations. The pattern of transmission is presented with a pedigree diagram. The patients were informed that data concerning the case would be submitted for publication, and they consented. Case 1. In 1981, an eleven-year-old Hispanic male without a relevant medical or surgical history presented after eighteen months of worsening pain in the lateral part of the left hip; the pain radiated to the knee and was aggravated by running. The patient did not report antecedent trauma, fevers, chills, or earlier symptoms. He did not report morning stiffness or other joint complaints. The family history was notable in that a great-grandfather reportedly had “hip problems” but was otherwise healthy. On examination, the patient was in the seventy-fifth percentile for weight and the fortieth percentile for height. There was decreased motion of the left hip, most marked in rotation and abduction (flexion, 100°; extension, −10°; abduction, 30°; internal rotation, 0°; and external rotation, 10°). Anterior groin pain was elicited with internal and external rotation maneuvers, and lateral hip pain was reported with extremes of flexion. Laboratory results demonstrated a normal hemoglobin level (133 g/L) …

Congenital pseudarthrosis is an uncommon anomaly poorly referred to in the pediatric literature. To describe congenital pseudarthrosis in children. We discuss the presentation, clinical symptomatology, and treatment. We reviewed the records of four children with congenital pseudarthrosis from 1990 to 2009 at the radiology department of Texas Scottish Rite Hospital for Children. Four girls ages 4 through 14 were identified. Three children presented with a bulge in the mid-clavicle as a chief complaint. The fourth child (14 years old) had bluish discoloration of the right upper extremity with venous distention. Three of the four did not have other abnormalities, while the 14-year-old had exostosis on the left hand. The mid-portion of the right clavicle was involved in all four children. Three of the four were treated surgically. Congenital pseudarthrosis of the clavicle is an uncommon anomaly found mostly in girls and in the mid-right clavicle.

Idiopathic scoliosis (AIS) is the most common pediatric spinal deformity, affecting ~3% of children worldwide. AIS significantly impacts national health in the U. S. alone, creating disfigurement and disability for over 10% of patients and costing billions of dollars annually for treatment. Despite many investigations, the underlying etiology of IS is poorly understood. Twin studies and observations of familial aggregation reveal significant genetic contributions to IS. Several features of the disease including potentially strong genetic effects, the early onset of disease, and standardized diagnostic criteria make IS ideal for genomic approaches to finding risk factors. Here we comprehensively review the genetic contri- butions to IS and compare those findings to other well-described complex diseases such as Crohn's disease, type 1 diabe- tes, psoriasis, and rheumatoid arthritis. We also summarize candidate gene studies and evaluate them in the context of possible disease aetiology. Finally, we provide study designs that apply emerging genomic technologies to this disease. Existing genetic data provide testable hypotheses regarding IS etiology, and also provide proof of principle for applying high-density genome-wide methods to finding susceptibility genes and disease modifiers.

Macrodystrophia lipomatosa is a rare form of congenital localized gigantism that is characterized by slowly progressive overgrowth of the mesenchymal elements, especially the fibroadipose tissue, in a limb1-3. The abnormal tissue is often found along the median nerve in the hand and the plantar nerves in the foot4,5. No causal link between hamartoma of a nerve and soft-tissue enlargement has been established, and evidence of nerve involvement is controversial. We report on two cases of macrodystrophia lipomatosa that caused progressive proximal enlargement along the posterior aspect of the left lower limb in one patient and along the anterior portion of the left upper limb in another. Our search of the literature revealed only one other previously reported case of such progressive enlargement, which was in a purely preaxial distribution6. Both of our patients were informed that information regarding their cases would be submitted for publication. Case 1. A four-month-old girl presented to the clinic with enlarged second and third toes on the left foot. The condition had been present at birth. The mother's pregnancy had been full term and unremarkable. There was no family history of limb malformations or neurofibromatosis. The patient was otherwise healthy and had a normal examination except for very enlarged second and third toes. Radiographs revealed increased soft-tissue density and enlargement of the second and third phalanges and metatarsals (Fig. 1-A). Resection of the second and third rays was performed when the patient was six months of age. Histologically, the resected specimens were enlarged but were otherwise normal in structure and had excessive amounts of normal-appearing adipose tissue. Postoperatively, the foot was noted to be similar in width and height to the contralateral, uninvolved foot. By three months after the operation, the mother noted enlargement …

Background: The treatment of Legg-Calve-Perthes disease has been based on uncontrolled retrospective studies with relatively small numbers of patients. This large, controlled, prospective, multicenter study was designed to determine the effect of treatment and other risk factors on the outcome in pa

Background: Accurate and reliable radiographic classifications of the relative severity and outcome of Legg-Calve-Perthes disease are essential in the study of that disease. As part of a prospective multicenter study*, we sought to define more clearly the lateral pillar classification of severity an

Idiopathic scoliosis (IS) affects approximately 2%-3% of the population and has a heritable component. The genetics of this disorder are complex. Here, we describe a family in which a pericentric inversion of chromosome 8 co-segregates with IS. We have used fluorescence in situ hybridization to identify cloned DNAs that span the breakpoints on the two arms of the chromosome. We have identified a bacterial artificial chromosome (BAC) of 150 kb that crosses the q-arm breakpoint and a BAC of 120 kb that crosses the p-arm breakpoint. The complete genomic DNA sequence of these BACs has been analyzed to identify candidate genes and to localize further the precise breakpoints. This has revealed that the p-arm break does not interrupt any known gene and occurs in a region of highly repetitive sequence elements. On the q-arm, the break occurs between exons 10 and 11 of the gamma-1 syntrophin (SNTG1) gene. Syntrophins are a group of cytoplasmic peripheral membrane proteins that associate directly with dystrophin, the Duchenne muscular dystrophy gene; gamma1-syntrophin has been shown to be a neuronal cell-specific protein. Mutational analysis of SNTG1 exons in 152 sporadic IS patients has revealed a 6-bp deletion in exon 10 of SNTG1 in one patient and a 2-bp insertion/deletion mutation occurring in a polypyrimidine tract of intronic sequence 20 bases upstream of the SNTG1 exon 5 splice site in two patients. These changes were not seen in a screen of 480 control chromosomes. Genomic DNAs from seven affected individuals within the family of a patient carrying the 6-bp deletion were typed to determine whether the alteration co-segregated with IS. The deletion was only observed in five out of these seven individuals. Thus, although genetic heterogeneity or multiple alleles cannot be ruled out, the 6-bp deletion does not consistently co-segregate with the disease in this family.

We report three infants with a poorly known form of congenital anterolateral angulation of the tibia with distinctive features seen on lateral roentgenograms. In these films the affected tibia appears to be divided into two segments, one proximal and the other distal, which taper as they approach each other at the site of the angulation, and end separately at the apex of the curve with an intervening radiolucent gap in the anterior tibial cortex. The two tibial segments are originally bridged and held firmly in that position by a well-defined triangular osseous structure located in the concavity of the tibial bow. It appears from the three cases reported in this paper and a few comparable cases in the literature that this form of tibial bowing is not prone to fracture followed by pseudoarthrosis and that it tends to improve (and resolve) spontaneously, with a resorption of the intramedullary bony structures at the apex of the curve resulting in the formation of a normal medullary cavity. A limb length discrepancy of varying degree is the main residual change of the anomaly.

Idiopathic scoliosis (IS) is a common paediatric musculoskeletal disease that displays a strong female bias. By performing a genome-wide association study (GWAS) of 3,102 individuals, we identify significant associations with 20p11.22 SNPs for females (P=6.89 × 10−9) but not males (P=0.71). This association with IS is also found in independent female cohorts from the United States of America and Japan (overall P=2.15 × 10−10, OR=1.30 (rs6137473)). Unexpectedly, the 20p11.22 IS risk alleles were previously associated with protection from early-onset alopecia, another sexually dimorphic condition. The 174-kb associated locus is distal to PAX1, which encodes paired box 1, a transcription factor involved in spine development. We identify a sequence in the associated locus with enhancer activity in zebrafish somitic muscle and spinal cord, an activity that is abolished by IS-associated SNPs. We thus identify a sexually dimorphic IS susceptibility locus, and propose the first functionally defined candidate mutations in an enhancer that may regulate expression in specific spinal cells., Girls are tenfold more likely than boys to require surgical treatment for idiopathic scoliosis, a common paediatric skeletal disorder. Here, Sharma et al. identify the first sexually dimorphic idiopathic scoliosis risk locus, and demonstrate that it may play a role in the regulation of spinal cells.

Background Adolescent idiopathic scoliosis (AIS) is a common rotational deformity of the spine that presents in children worldwide, yet its etiology is poorly understood. Recent genome-wide association studies (GWAS) have identified a few candidate risk loci. One locus near the chromosome 10q24.31 LBX1 gene (OMIM #604255) was originally identified by a GWAS of Japanese subjects and replicated in additional Asian populations. To extend this result, and to create larger AIS cohorts for the purpose of large-scale meta-analyses in multiple ethnicities, we formed a collaborative group called the International Consortium for Scoliosis Genetics (ICSG). Methods Here, we report the first ICSG study, a meta-analysis of the LBX1 locus in six Asian and three non-Asian cohorts. Results We find significant evidence for association of this locus with AIS susceptibility in all nine cohorts. Results for seven cohorts containing both genders yielded P=1.22×10–43 for rs11190870, and P=2.94×10–48 for females in all nine cohorts. Comparing the regional haplotype structures for three populations, we refined the boundaries of association to a ∼25 kb block encompassing the LBX1 gene. The LBX1 protein, a homeobox transcription factor that is orthologous to the Drosophila ladybird late gene, is involved in proper migration of muscle precursor cells, specification of cardiac neural crest cells, and neuronal determination in developing neural tubes. Conclusions Our results firmly establish the LBX1 region as the first major susceptibility locus for AIS in Asian and non-Hispanic white groups, and provide a platform for larger studies in additional ancestral groups.

Genetic studies of orthopaedic conditions, particularly those of childhood onset, enjoyed many successes in the early days of disease gene discovery. Some of the earliest high-profile discoveries centered on diseases with skeletal manifestations, such as neurofibromatosis1,2, achondroplasia3,4, and brachydactyly5-8. These successes were largely attributable to the availability of extended families with multiple affected members. Multigenerational families were informative in linkage mapping, also called inheritance mapping (Table I). Linkage mapping is an unbiased approach that seeks to identify genomic regions and genes that are inherited or “linked” among all affected members of the family. Linkage mapping proved particularly powerful for solving diseases that (1) have Mendelian inheritance, being caused by a single mutation in a family; (2) display high penetrance, such that essentially all family members with the mutation show the disease; and (3) are prevalent enough to permit the identification of several extended families. Linking a disease to a specific region of the genome was an important milestone for many early genetic studies, with such highlights as the mapping of the neurofibromatosis-1 gene (NF1) to chromosome 17q11.2 and the achondroplasia gene (FGFR3, which encodes fibroblast growth factor receptor 3) to 4p16.3. Once linkage mapping focused attention on a particular genomic region, the next major step in discovery was analysis of the region to identify the culprit gene harboring a disease-causing mutation. This process was labor and resource-intensive because linked regions were typically large and poorly annotated and encoded numerous genes9. A now classic, and celebrated, example of the immense effort required to find a disease mutation is the almost ten-year search for the Huntington disease gene10. Nevertheless, the combination of linkage mapping and individual gene sequencing in families, traditionally called positional cloning, was highly …

This study involved the mechanical testing of single-rod segmental hook fixation and double-rod segmental hook fixation in a long-segment animal model. The goals were first to compare the flexibility of a single-rod scoliosis construct with that of a double-rod construct when tested in torsion, and second, to determine the effect of not using instrumentation with every vertebral segment for the single rod. Another study found that the single-rod construct was as stiff in torsion as the standard double-rod construct in a model of 10 vertebral segments. The amount of neutral zone (NZ) rotation was tested in five calf spines using an MTS (Material Testing System) machine. Five constructs were tested and included 1) a single rod with hooks at every level except the apex; 2) a single rod with two fewer hooks; 3) a single rod with four fewer hooks; 4) a double-rod construct; and 5) no instrumentation. The amount of NZ rotation between vertebral segments was measured over 12, 10, 8, 6, 4, and 2 vertebral segments. An analysis of variance with all constructs showed that the instrumented spines had significantly less movement than did the uninstrumented spine. Statistical comparison using analysis of variance of constructs (constructs 1 to 4) showed that over 12 vertebral segments (T4-L3), all single-rod constructs (constructs 1 to 3) allowed more NZ rotation than did the standard double-rod construct. This testing indicated that over 12 vertebral segments the single rod allowed more NZ rotation than a double-rod construct.

Study Design. A consecutive series of patients with idiopathic scoliosis treated with single-rod instrumentation was followed prospectively. Outcomes were compared with results obtained from a retrospective review of a consecutive series of patients treated with double-rod instrumentation. Objective. To compare single-rod instrumentation with segmental fixation with double-rod instrumentation for the treatment of adolescent idiopathic scoliosis. Summary of Background Data. Mechanical testing of single-rod instrumentation with segmental fixation at every level showed it to be as resistant to torsion as a double-rod construct. A clinical trial was initiated to document the clinical outcome in single-rod patients. Methods. A total of 43 of 51 consecutive patients underwent spinal fusion with a single rod. Outcome was evaluated at a minimum of 2 years after surgery. The control group comprised 103 patients who had standard double-rod instrumentation at the same institution. Results. The single- and double-rod groups were similar with respect to age, sex, curve type, length of follow-up, curve magnitude, and best bend. For King III–V curves undergoing posterior spinal fusion, there was significantly less blood loss in the single-rod group (703 mL vs 1011 mL), less cell saver collection (189 mL vs 367 mL), and less operating time (220 minutes vs 260 minutes). Blood loss and operating time were not different for patients with King I and King II curves. There were eight patients (19%) requiring reoperation because of hardware-related problems in the single-rod group compared with four (4%) in the double-rod group. There were nine patients (21%) with broken rods in the single-rod group, six of whom were symptomatic and five of whom required reoperation. Two patients required multiple operations because of pseudarthrosis in the single-rod group. There were no broken rods in the double-rod group. The single-rod group had 2 early postoperative infections and no late infections compared with 10 late infections in the double-rod group. There was a statistically significant relationship between hardware problems and fusion below L1 in the single-rod group. Conclusion. Because of rod failure, single-rod instrumentation should be considered only in curves that can be instrumented to L1 and higher.

Background: Our aim was to compare height velocity data, obtained from clinical height measurements, for girls who had idiopathic scoliosis with the data for adolescents who did not have scoliosis. We also compared the growth data with chronological age, menarchal age, and Risser sign in terms of their accuracy in the prediction of growth and progression of the scoliosis. Methods: One hundred and twenty of 371 patients in a database of girls managed with a brace for the treatment of idiopathic scoliosis had sufficient height data for us to quantify their growth peak. Height velocity data was generated from standing-height measurements obtained, in a scoliosis clinic, with a minimum six-month interval between measurements, and the timing of peak height velocity was calculated. The age at menarche was recorded from the patients' records. The Risser sign and Cobb angle were determined by a single observer. Progression of the scoliosis was defined as an increase in the Cobb angle of at least 10 degrees, compared with the curve magnitude at the time of the initial evaluation, after a minimum of six months. Progression to a magnitude requiring surgery was defined as progression of at least 10 degrees to a magnitude of 45 degrees or more. Results: The height velocity plot grouped by peak height velocity showed a high peak and a sharp decline with values similar to those in normal populations. Extrapolating from percentile charts, 90 percent of our patients ceased growing by 3.6 years after peak height velocity. The growth peak was blunted (averaged over too long a period such that the data for the period of most rapid growth was averaged in with that for a period of slower growth) when chronological age, menarchal age, and Risser sign were used to predict growth; this indicated that these maturity scales grouped the patients poorly in terms of growth. The primary curve was progressive in eighty-eight of the 120 patients. Sixty of these patients had a curve of more than 30 degrees at peak height velocity, and in fifty (83 percent) of the sixty the curve progressed to 45 degrees or more. The remaining twenty-eight patients had a curve of 30 degrees or less at peak height velocity, with only one curve (4 percent) progressing to 45 degrees or more. Peak height velocity also grouped patients for maximal progression of the curve more accurately than did the other maturity scales, as most of the curves progressed maximally at peak height velocity. There was a wider spread of timing of maximal progression when chronological age, menarchal age, and Risser sign were used to predict progression. Conclusions: Height velocities generated from clinical height measurements for patients with idiopathic scoliosis document the growth peak and predict cessation of growth reliably. Knowing the timing of the growth peak provides valuable information on the likelihood of progression to a magnitude requiring spinal arthrodesis.

Background. This paper reports three children with short stature: developmental coxa vara unilateral in the first case and bilateral in the other two; somewhat squared and “ovoid” vertebral bodies in the first patient, and normal to slightly tall vertebral bodies in the third; metaphyseal changes in some long tubular bones including bone fragments similar to the corner fractures seen in child abuse in all three patients.¶Materials and methods. The first and second patients were sisters; their mother, also quite short, had surgical procedures in early life for bilateral “coxa vara”; their brother, also of short stature, had bilateral coxa valga with otherwise normal femoral heads and necks, and mild metaphyseal changes associated with two minute “corner fractures” in the proximal metaphysis of the left tibia.¶Results. A review of reported cases of developmental coxa vara associated with spondylometaphyseal dysplasia revealed that simulated corner fractures were present in most instances.

Over the past ten years, a subfield of GIScience has been recognized that addresses the linkage between human thought regarding geographical space, and the mechanisms for implementing these concepts in computational models. This research area has developed an identity through a series of successful international conferences and the establishment of a journal. It has also been complemented through community activities such as international standardization efforts and GIS interoperability. Historically, much of the advancement in computational methods has occurred at or close to the implementation level, as exemplified by attention to the development of spatial access methods. Significant progress has been made at the levels of spatial data models and spatial query languages, although we note the lack of a comprehensive theoretical framework comparable to the relational data model in database management systems. The difficult problems that need future research efforts are at the highly abstract level of cap...

Springtime measurements of NOx, ozone, PAN,J(NO2), and other compounds were made near Ny-Alesund,Svalbard (78°54′N, 11°53′E), in 1994 and Poker Flat,Alaska (65°08′N, 147°29′W), in 1995. At Svalbard medianmixing ratios for PAN and NOx of 237 and 23.7 pptv,respectively, were observed. The median mixing ratios at Poker Flat for PANand NOx were 79.5 and 85.9 pptv, respectively. These data areused to estimate thermal PAN decomposition using several differentapproaches. At Svalbard PAN decomposition was very small, while at PokerFlat up to 30 pptv/h PAN decomposed. At both sites the NOx/PANratio increased with temperature between –10 and 20°C implyingthat PAN decomposition is an important NOx source. In-situozone production was calculated from the measured NO, NO2,O3, J(NO2), and temperature data, using thesteady state assumption Median ozone production was 605 pptv/h at PokerFlat, and one order of magnitude smaller at Svalbard during the daytime.Only at Poker Flat could a direct influence on the diurnal ozone cycle beobserved from in-situ production. These results imply that PAN decompositionis a major source of NOx in the high latitude troposphere, andthat this contributes to the observed spring maximum in surface ozone.

A seven-year record of surface ozone measurements from Denali NationalPark, Alaska shows a persistent spring maximum. These data, combined withmeasurements of NOx, hydrocarbons, O3, and PANfrom a continental site in Alaska during the spring of 1995 are used as thebasis for a sensitivity study to explore tropospheric photochemistry in thisregion. Because of the relatively high concentrations of NOx(mean of 116, median of 91 pptv), the net tendency was for photochemicalozone production. The range of net O3 production for averageconditions measured at this site during spring is between 0.96–3.9ppbv/day depending on the assumptions used; in any case, this productionmust contribute to the observed springtime maximum in O3.Model calculations showed that of the anthropogenic ozone precursors, onlyNOx had a strong effect on the rate of ozone production; themeasured concentrations of anthropogenic hydrocarbons did not significantlyaffect the ozone budget. Naturally produced biogenic hydrocarbons, such asisoprene, may also have a significant effect on ozone production, even atconcentrations of a few 10's of pptv. An observed temperature-isoprenerelationship from a boreal site in Canada indicates that isoprene may bepresent during the Alaskan spring. Measurements of isoprene taken duringthe spring of 1996 suggest that reactive biogenic hydrocarbon emissionsbegin before the emergence of leaves on deciduous trees and that theconcentrations were sufficient to accelerate ozone production.

Sequencing technologies promising the “$1000 genome” have developed at a staggering pace, driven in part by the HapMap Project1 (which set out to catalog common variations throughout the genome in multiple ethnic populations) and the 1000 Genomes Project2 (a consortium to catalog rare variations from different ethnic populations worldwide). Commercial whole-genome sequencing platforms have yet to break the $1000 mark. However, sequencing throughput and accuracy are no longer limiting factors. Despite recent successes in patient-oriented whole-genome sequencing3-6, analyzing and interpreting these data sets represent a major challenge, particularly for the ∼98% of the genome that does not encode proteins. In 2009, an alternative to whole-genome sequencing was introduced7. Whole-exome sequencing uses high-throughput next-generation technologies to sequence only the portions of the genome that encode proteins (termed the exome). The goal of whole-exome sequencing is to identify sequence mutations that alter the amino acid content of a protein, potentially altering the protein’s function in a cell and leading to disease. Proof of concept for this approach was documented in a landmark paper that used whole-exome sequencing to identify the genetic cause of Freeman-Sheldon syndrome (OMIM [Online Mendelian Inheritance in Man] 193700)7. This study broke the technical and cost limitation barriers (compared with sequencing an entire genome) by sequencing only the protein-coding regions (∼1% of the genome) and showed that a study of only a few patients was sufficient to identify a disease-causing gene. Whole-exome sequencing has revolutionized disease-gene discovery and, supported by the 1000 Genomes Project2 and other large-scale sequencing studies (e.g., the NHLBI/NHGRI [National Heart, Lung, and Blood Institute/National Human Genome Research Institute] Exome Project), it promises to identify virtually all genes causing disorders with Mendelian inheritance—i.e., those disorders caused by single genes. In this review, we focus on …

The cause of Legg-Calvé-Perthes disease (LCPD) is unknown. We have observed a relatively high prevalence of female gymnasts presenting with LCPD. The purpose of this study was to determine: (1) the percentage of LCPD patients exposed to high-level gymnastics training, (2) the demographics of this subset of patients, and (3) their clinical outcomes.Several adolescent female gymnasts presented to our clinic with recent-onset LCPD. We reviewed our cases to discern the prevalence and treatment of the disorder in this patient cohort. From 1999 to 2010, 572 patients were evaluated for a diagnosis of LCPD at our tertiary referral center. Clinical records were retrospectively reviewed. Of those, 13 patients had a history of gymnastics participation with 8 patients (all females) having competitive participation.For females aged 10 years and older presenting with LCPD, 7 of 9 patients (78%) were involved in high-level competitive gymnastics. These patients had disease onset between 10 and 12 years of age (mean, 11 y). Competitive gymnasts represented 6.6% (8 of 120) of females with LCPD and 1.4% (8 of 572) of all patients evaluated with LCPD during the study period. Only 1 of 111 females below 10 years with LCPD participated in competitive gymnastics (χ, P0.0001).Patients underwent a variety of treatments. Two patients underwent nonoperative treatment, and the remainder underwent surgical management. All 7 gymnasts had a Stulberg IV result. In the nongymnast group of females 10 years and older, there were 1 Stulberg III result and 1 Stulberg IV result.At our center, competitive gymnasts comprise75% of the female patients over the age of 10 who presented with late-onset LCPD. Results in general were poor. Further studies are needed to explore the association between the physical demands of advanced gymnastic training and the development of LCPD in this subset of patients.IV, case series.

Background Current radiographic prognosticators of the outcome of Perthes disease can only be applied after femoral head deformity has occurred. Quantification of femoral head perfusion using the gadolinium-enhanced subtraction magnetic resonance imaging (MRI) technique may serve as an early prognosticator of outcome. The purposes of this study were 2-fold: (1) to develop a reliable method to quantify femoral head perfusion using this MRI technique; and (2) to determine whether the perfusion at early stages of Perthes disease correlates with radiographic deformity after a 2-year follow-up. Methods A total of 20 patients meeting the following inclusion criteria were studied: radiographs and MRI obtained of femoral heads predeformity, age between 5 and 13 years, and unilateral disease. MR perfusion index, a measure of perfusion in the epiphysis, was obtained using digital image analysis of subtraction gadolinium-enhanced MRI. Intraobserver and interobserver agreement of this index was assessed by 2 independent observers. MR perfusion index was correlated with a radiographic deformity index (a measure of femoral head deformity) obtained after a minimum of 2 years. Results The intraobserver agreement assessed by the intraclass correlation coefficient was 0.96 for observer 1 and 0.97 for observer 2. The interobserver agreement of the MR perfusion index was 0.90 for trials 1 and 2. MR perfusion index in the early stages of Perthes disease was highly variable, ranging from 0 to 0.70. After a minimum of 2 years following MRI acquisition, radiographs were obtained and evaluated using the deformity index, a continuous measure of femoral head deformity, by 2 blinded observers. Deformity index at 2-year follow-up showed moderate correlation with predeformity MR perfusion index (r=-0.56, P=0.01, R=0.31). In those patients who were treated nonoperatively, the correlation was stronger (r=-0.79, P=0.006, R=0.63). Conclusions MR perfusion index obtained from gadolinium-enhanced subtraction MR images showed a high interobserver agreement. MR perfusion index is highly variable at early stages of Perthes disease, and a lower MR perfusion index correlated with greater radiographic deformity at the 2-year follow-up. This pilot study shows the promise of predeformity MR perfusion index as a possible early prognosticator of outcome in Perthes disease. Levels of evidence Prognostic level II.

Knowledge of genes influencing longitudinal patterns may offer information about predicting disease progression. We developed a systematic procedure for testing association between SNP genotypes and longitudinal phenotypes. We evaluated false positive rates and statistical power to localize genes for disease progression. We used genome-wide SNP data from the Framingham Heart Study. With longitudinal data from two real studies unrelated to Framingham, we estimated three trajectory curves from each study. We performed simulations by randomly selecting 500 individuals. In each simulation replicate, we assigned each individual to one of the three trajectory groups based on the underlying hypothesis (null or alternative), and generated corresponding longitudinal data. Individual Bayesian posterior probabilities (BPPs) for belonging to a specific trajectory curve were estimated. These BPPs were treated as a quantitative trait and tested (using the Wald test) for genome-wide association. Empirical false positive rates and power were calculated. Our method maintained the expected false positive rate for all simulation models. Also, our method achieved high empirical power for most simulations. Our work presents a method for disease progression gene mapping. This method is potentially clinically significant as it may allow doctors to predict disease progression based on genotype and determine treatment accordingly.

During late spring of 1991, airborne measurements in the smoke plume from the Kuwait oil fires indicated that SO2 was removed from the gas phase at rates of ∼6 to 8% h−1 and that NOx was removed at rates of ∼7 to 23% h−1. Photochemical calculations indicate that homogeneous chemical reactions were responsible for only a small fraction of this removal. Also, indirect evidence suggests that heterogeneous removal of SO2 on black carbon (or soot) and salt aerosols produced by the fires was relatively slow. The highest rates of SO2 and NOx removal were associated with high concentrations of atmospheric soil dust. This was likely due to heterogeneous oxidation of the SO2 and NOx on the surfaces of soil dust particles. The removal of SO2 and NOx on soil dust was probably accelerated by the alkaline nature of the dust. Heterogeneous reactions on soil dust particles proceeded more rapidly in regions of dispersed smoke than in the core of the plume; this was probably due to the depletion of the available surface area of the soil dust in regions of dense smoke. On the basis of smoke samples collected during the experiment we estimate that the quasi-second-order reaction rate for SO2 is (9 ± 4) × 10−8 (μg soil dust m−3)−1 s−1. For a soil dust concentration of 200 μg m−3 this implies a removal rate for SO2 on soil dust of 6.5% h−1.

Two children with spastic quadriplegia who developed excessive lumbar lordosis after selective dorsal rhizotomy are described. The rhizotomy did not change the ambulatory status of either child (one nonambulator, one household ambulator). Preservation of unopposed hip flexion in the presence of multiple laminectomies may lead to the development of a lordotic deformity in children who sit most of the time. Excessive lumbar lordosis may cause pain and difficulty in sitting. Surgical correction of this deformity is complex because of the removal of posterior elements during the rhizotomy.

We performed a retrospective study of the long-term results of posterior instrumentation and arthrodesis of the spine in forty-three patients who had idiopathic scoliosis and a Risser grade of 0 at the time of the operation. The average age of the patients was 12.4 years (range, 6.7 to 15.5 years) at the time of the operation. The triradiate cartilages were open in twenty-three patients and closed in twenty. At the time of the latest follow-up evaluation (average duration of follow-up, four years; range, two to eleven years), seventeen patients had a Risser grade of 5; twenty-two, 4; two, 3; one, 2; and one, 0. The crankshaft phenomenon, a progressive deformity resulting from continued growth of the anterior aspect of the spine after posterior arthrodesis, was seen in only one patient who had closed triradiate cartilages and in ten patients who had open triradiate cartilages (p = 0.004). The most common radiographic finding was a progressive rib-vertebra angle difference, which increased more than 10 degrees in seven of the eleven patients who had the crankshaft phenomenon. The mean increase in these eleven patients was 22 degrees, compared with no increase in the thirty-two other patients (p < 0.0001). Open triradiate cartilages (r = 0.58, p = 0.0001) and a younger age at the time of the operation (p < 0.0001) were predictive of the amount of progression as a result of the crankshaft phenomenon. In patients who had open triradiate cartilages, less skeletal maturity was also predictive of progression as a result of the crankshaft phenomenon (r = -0.72, p = 0.0002).

In this study of patients with right thoracic scoliosis, the outcomes of spinal instrumentation and fusion are compared between those with syringomyelia-related deformity and those with adolescent idiopathic scoliosis. The syringomyelia group included all patients treated for that condition at a given institution and a given time period, whereas the idiopathic cases were selected to match the syringomyelia group with respect to age, sex, and curve characteristics. The outcomes of surgery, including deformity-related measures of curve severity, balance, flexibility, overall correction, and loss of correction, were quite similar in the two groups. A minor difference was that more patients with syringomyelia had proximal junctional kyphosis (14% versus 6% in the idiopathic group), which the authors related to the need to correct excessive kyphosis in the syringomyelia group. Patient-reported outcomes were also equivalent in the two groups. The selection of the groups for comparison deserves some comment. Syrinx-related scoliosis, as reported, usually affects boys as often as girls, whereas idiopathic scoliosis is much less common in males. Surgical correction has been reported to be more difficult in males, which …

Background: Long-term studies have indicated good outcomes for most patients with Legg-Calve-Perthes disease. However, clinical experience suggests that less favorable outcomes are common. We sought to prospectively document pain and function in a cohort of adults who had previously been treated nonoperatively for Legg-Calve-Perthes disease. Methods: Patients in our region with Legg-Calve-Perthes disease were enrolled between 1984 and 1991 as part of a multicenter prospective trial and were treated with hip range-of-motion exercises or bracing. Patients returned for physical examination, radiographs, and completion of outcome measures including the Nonarthritic Hip Score (NAHS) and the Iowa Hip Score (IHS). Results: Fifty-six patients (fifty-eight hips) were examined at a mean of 20.4 years (range, 16.3 to 24.5 years) after enrollment. The mean NAHS was 79 (range, 35 to 100), and the mean IHS was 74 (range, 43 to 100). Three patients had required hip arthroplasty and one patient had required a pelvic osteotomy. Fourteen (26%) of the remaining hips had no hip osteoarthritis, sixteen (30%) had mild osteoarthritis (Tonnis grade 1), and twenty-four (44%) had moderate or severe osteoarthritic changes on radiographs (grade 2 or 3). Femoroacetabular impingement indicated by physical examination was associated with pain and with poorer outcomes on the IHS and the NAHS (p = 0.0004, 0.0014, and 0.0007, respectively). The Stulberg classification was significantly associated with impingement on physical examination (p = 0.0495), the NAHS (p = 0.003), and the Tonnis grade (p = 0.012). Multivariate logistic regression showed that only the Stulberg classification was significantly associated with the NAHS (p = 0.0032); the odds ratio for a Stulberg type of I or II compared with IV or V in patients with a fair or poor NAHS was 0.101 (95% confidence interval, 0.018 to 0.573). Conclusions: Pain, arthritis, and ongoing hip dysfunction are common in patients with Legg-Calve-Perthes disease that was treated nonoperatively. Hips rated as Stulberg type III or IV more frequently had poor or fair outcomes on the IHS and NAHS (61% and 72% for type III and 77% and 60% for type IV). Patients with a lateral pillar type of B, B/C, or C frequently had pain and radiographic evidence of osteoarthritis. Clinical signs of femoroacetabular impingement were associated with pain and with lower functional scores. This prospective study establishes a modern benchmark for outcomes following nonoperative, weight-bearing treatment of Legg-Calve-Perthes disease. Level of Evidence: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.

STUDY DESIGN To determine the effectiveness of posterior TSRH instrumentation for the treatment of idiopathic scoliosis, 103 patients with a 2-year minimum followup were retrospectively studied. METHODS Patients who underwent operations between October 1988 and April 1991 were evaluated for curve correction, spinal balance, and complications. Age at surgery averaged 14.3 years. Follow-up averaged 2.5 years. RESULTS Thoracic curve correction averaged 65% in those with King Type III/IV curves and 54% in those with Type II curves. With follow-up, correction loss averaged approximately 13% for each group. Lumbar curve correction after instrumentation in Type I and II curves averaged 48% postop but lost approximately 20% with follow-up. Trunk balance improved 77% toward midline after surgery in those with Type III/IV curves. Improvement in trunk balance was less impressive in patients with Type II curves, particularly after selective thoracic fusions. Thoracic sagittal contour improved 43% for hypokyphotic (< 20 degrees) patients but, in the remainder, no significant radiographic change was evident. No neurologic complications occurred. Delayed deep infections developed in ten patients (10%) between 11 and 45 months postoperative. Cultures eventually grew Propionibacterium acnes, staph epidermidis, or staph coagulase negative in eight patients. Two patients had pseudarthroses. CONCLUSIONS Frontal and sagittal thoracic curve correction can be satisfactorily obtained using TSRH instrumentation. Continued efforts are being made to improve lumbar hook patterns and technique to achieve and maintain better lumbar curve correction.