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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.

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.

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.

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.

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.

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.

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.

Background: A gene for Larsen syndrome was recently described, and mutations were reported in five cases. Objective: To test whether mutations in this gene, FLNB , could explain the disease in our independent collection of sporadic and dominant Larsen syndrome cases; and to test whether mutations occurred in a non-random pattern. Results: Missense mutations were found in each of five cases. Four of the five were new; one was reported in a sporadic case in the original Larsen syndrome study of five cases. All mutations from the two studies were compiled. Clustered mutations were observed within three filamin B protein domains: the calponin homology 2 domain, repeat 14, and repeat 15. This suggested that as few as five (of the total of 46) coding exons of FLNB could be screened to detect Larsen syndrome mutations. Four of these exons were screened in a sixth (sporadic) case and a previously reported G1691S substitution mutation detected. Conclusions: Mutations in FLNB may be responsible for all cases of Larsen syndrome. They appear to occur in specific functional domains of the filamin B protein. This should simplify diagnostic screening of the FLNB gene. Analyses in larger patient series are warranted to quantify this. The study confirmed the extreme variability in clinical presentation and the presence of unaffected carriers. A molecular screen would be valuable for diagnosis and genetic counselling.

Children with physical disabilities are often treated in physical therapy without a parent present, under the assumption that the parent may "interfere" with therapy and/or the child will be too distracted if a parent is present. The effectiveness of a therapy program with parental involvement was compared to a program without parents involved. Results indicate that training with the mother present was as effective as training without the mother. Our data showed that therapists working with parents can accomplish the goal of therapy in a shorter time period than when the child is treated without the parent.

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In such procedures as the Harrington operation for idiopathic scoliosis, evaluation of spinal cord function is advisable immediately after the back is straightened. The authors have used hypnosis for this procedure, as an adjunct to anesthetic management. Patients are awakened on the table, given lower extremity tests, and are then reanesthetized. The incidence of postoperative pain and other discomfort is also reduced by hypnosis.

* We Americans have used the handy phrase "technical assistance" abroad to cover a multitude of things that don't fall into crisp categories. The phrase leaves much untold. When we enter other countries at earth level and attempt to share with the inhabitants in the intimate and pressing matters that are the very stuff of their lives and social ways, we are submitting ourselves to the most sensitive testing of our humility and our wisdom. Neither innocence abroad nor arrogance abroad is tolerable. True friendship abroad, is. The venture described here is one of the most imaginative of the international jobs in which America shares, for it is based on that highly elusive but commanding premise, the soundness of the community method. And its difficulty can be gauged by the fact that this is no easy export of a commodity in which our country admittedly excels, but is rather a vision of human dealing in which we are but one of the gropers. This of course lifts the Sardinian venture cleanly out of the basket of things we do "for foreigners" and daringly onto the plane of values we pursue with our friends. It is superfluous to add that the wide success of this approach the world around might cause peace to break out in unexpected places.