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High-constitutive activity of the DNA damage response protein checkpoint kinase 1 (CHK1) has been shown in glioblastoma (GBM) cell lines and in tissue sections. However, whether constitutive activation and overexpression of CHK1 in GBM plays a functional role in tumorigenesis or has prognostic significance is not known. We interrogated multiple glioma patient cohorts for expression levels of CHK1 and the oncogene cancerous inhibitor of protein phosphatase 2A (CIP2A), a known target of high-CHK1 activity, and examined the relationship between these two proteins in GBM. Expression levels of CHK1 and CIP2A were independent predictors for reduced overall survival across multiple glioma patient cohorts. Using siRNA and pharmacologic inhibitors we evaluated the impact of their depletion using both in vitro and in vivo models and sought a mechanistic explanation for high CIP2A in the presence of high-CHK1 levels in GBM and show that; (i) CHK1 and pSTAT3 positively regulate CIP2A gene expression; (ii) pSTAT3 and CIP2A form a recursively wired transcriptional circuit; and (iii) perturbing CIP2A expression induces GBM cell senescence and retards tumor growth in vitro and in vivo . Taken together, we have identified an oncogenic transcriptional circuit in GBM that can be destabilized by targeting CIP2A. IMPLICATIONS: High expression of CIP2A in gliomas is maintained by a CHK1-dependent pSTAT3-CIP2A recursive loop; interrupting CIP2A induces cell senescence and slows GBM growth adding impetus to the development of CIP2A as an anticancer drug target., (©2020 American Association for Cancer Research.)

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Ocular complications of adenotonsillectomy are rare. The authors describe a 6-year-old boy who developed mydrasis and limitations of supraduction and infraduction after adenotonsillectomy. This was attributed to the hemorrhagic compression of the nerve in the cavernous sinus. This is the first report of pupil-involving oculomotor nerve palsy following adenotonsillectomy. [J Pediatr Ophthalmol Strabismus. 2019;56:e76-e78.]., (Copyright 2019, SLACK Incorporated.)

Systemic lupus erythematous (SLE) is a heterogeneous autoimmune disease in which outcomes vary among different racial groups. Here, we aim to identify SLE subgroups within a multiethnic cohort using an unsupervised clustering approach based on the American College of Rheumatology (ACR) classification criteria. We identify three patient clusters that vary according to disease severity. Methylation association analysis identifies a set of 256 differentially methylated CpGs across clusters, including 101 CpGs in genes in the Type I Interferon pathway, and we validate these associations in an external cohort. A cis-methylation quantitative trait loci analysis identifies 744 significant CpG-SNP pairs. The methylation signature is enriched for ethnic-associated CpGs suggesting that genetic and non-genetic factors may drive outcomes and ethnic-associated methylation differences. Our computational approach highlights molecular differences associated with clusters rather than single outcome measures. This work demonstrates the utility of applying integrative methods to address clinical heterogeneity in multifactorial multi-ethnic disease settings.

Objectives: We assessed the growth, distribution, and characteristics of pediatric intensive care in 2016., Design: Hospitals with PICUs were identified from prior surveys, databases, online searching, and clinician networking. A structured web-based survey was distributed in 2016 and compared with responses in a 2001 survey., Setting: PICUs were defined as a separate unit, specifically for the treatment of children with life-threatening conditions. PICU hospitals contained greater than or equal to 1 PICU., Subjects: Physician medical directors and nurse managers., Interventions: None., Measurements and Main Results: PICU beds per pediatric population (< 18 yr), PICU bed distribution by state and region, and PICU characteristics and their relationship with PICU beds were measured. Between 2001 and 2016, the U.S. pediatric population grew 1.9% to greater than 73.6 million children, and PICU hospitals decreased 0.9% from 347 to 344 (58 closed, 55 opened). In contrast, PICU bed numbers increased 43% (4,135 to 5,908 beds); the median PICU beds per PICU hospital rose from 9 to 12 (interquartile range 8, 20 beds). PICU hospitals with greater than or equal to 15 beds in 2001 had significant bed growth by 2016, whereas PICU hospitals with less than 15 beds experienced little average growth. In 2016, there were eight PICU beds per 100,000 U.S. children (5.7 in 2001), with U.S. census region differences in bed availability (6.8 to 8.8 beds/100,000 children). Sixty-three PICU hospitals (18%) accounted for 47% of PICU beds. Specialized PICUs were available in 59 hospitals (17.2%), 48 were cardiac (129% growth). Academic affiliation, extracorporeal membrane oxygenation availability, and 24-hour in-hospital intensivist staffing increased with PICU beds per hospital., Conclusions: U.S. PICU bed growth exceeded pediatric population growth over 15 years with a relatively small percentage of PICU hospitals containing almost half of all PICU beds. PICU bed availability is variable across U.S. states and regions, potentially influencing access to care and emergency preparedness.

Purpose: Three-dimensional printing has produced customized bolus during radiation therapy for superficial tumors along irregular skin surfaces. In comparison, traditional bolus materials are often difficult to manipulate for a proper fit. Current 3-dimensional printed boluses are made from either preexisting computed tomography scans or complex surface scanning methods. Herein, we introduce an inexpensive, convenient approach to generate a 3-dimensional printed bolus from surface scanning technology available in common smartphones., Methods and Materials: A three-dimensional printed bolus was designed using surface scans from iPhone X true depth cameras and a low-cost 3-dimensional printer. The percentage density infill was adjusted to achieve tissue equivalence. To evaluate the clinical feasibility, fit against the skin surface and radiation dose distribution were compared with those of the traditional bolus., Results: We fabricated a customized 3-dimensional printed bolus for different areas of the face using an iPhone X camera and inexpensive commercially available 3-dimensional printer. When printed at 100% density, the bolus material approximated soft tissue/water and provided an equivalent dose distribution to that found with standard bolus materials on direct comparison. The bolus material is inexpensive and produces an ideal fit with the scanned anatomy., Conclusions: We present a simplified method of highly customized bolus production that requires minimal experience with computer modeling programs and can be accomplished with an iPhone true depth camera., (Copyright © 2019 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Effective treatments that extend survival of malignant brain tumor glioblastoma (GBM) have not changed in more than a decade; however, there exists a minority patient group (<5%) whose survival is longer than 3 yr. We herein present a case report of a long-term surviving 51-yr-old female diagnosed with a MGMT unmethylated GBM. The patient was progression-free for 23 mo. Fresh primary and recurrent tumor samples were collected and processed for patient-derived model development. Whole-genome sequencing (WGS) was performed concurrently with additional standard of care diagnostics. WGS revealed a hypermutated genotype in the germline tissue and in both the primary and recurrent tumor samples. Specific to the matched tumors, an average of 30 cancer driver genes were mutated. Noteworthy was the identification of a nonsynonymous mutation in the POLE gene. As a possible instigator of the hypermutational genotype observed in the tumors, we identified nonsynonymous germline mutations within the mismatch repair genes, MLH1 and PMS2 Mutations within these genes are often indicative of the pan-cancer phenotype known as Lynch syndrome; however, their pathogenicity remains unreported. We performed a drug screen of 165 compounds, which identified one compound, YM155, an experimental survivin inhibitor, that showed effectivity to the patient-derived cell lines of both tumors. Treatment selection based on a patient's genome to individualize treatment for GBM patients could potentially be useful in the clinic. This is a promising avenue for further translational research, with larger databases and integrated platforms to increase the efficiency of analyzing and interpreting the individual genomic data of GBM., (© 2019 Jue et al.; Published by Cold Spring Harbor Laboratory Press.)

Objectives: The aim of this study was to compare differences in perception and knowledge of child abuse and child disciplinary practices according to the history of child abuse victimization., Methods: A questionnaire survey on child abuse was conducted with 491 adults raising children. We compared the perception and knowledge of child abuse and child disciplinary practices between two groups of adults with and without a history of childhood abuse victimization., Results: The group with a history of childhood abuse had lower levels of knowledge of child abuse (F=6.990, p<0.01) and engaged in more negative disciplinary practices (F=5.974, p<0.05) than those without. However, no differences in the perception of child abuse were observed between the two groups., Conclusion: The results suggest that adults with a history of childhood abuse have lower levels of knowledge of child abuse and use more negative disciplinary practices in raising their children. This highlights the need to administer not only educational but also more direct hands-on interventions to vulnerable parents in order to foster healthy parenting and disciplinary practices., Competing Interests: Conflicts of Interest The authors have no potential conflicts of interest to disclose., (Copyright: © Journal of the Korean Academy of Child and Adolescent Psychiatry.)

Untreated obstructive sleep apnea in children is associated with significant medical and psychological morbidities. Polysomnographic testing is the gold-standard method for diagnosis of obstructive sleep apnea. However, laboratory-based polysomnography is expensive and associated with a substantial healthcare burden. Thus, a simple valid tool to accurately identify those at high risk of obstructive sleep apnea is essential. We performed a retrospective cross-sectional study of children referred to the Youthdale Child and Adolescent Sleep Clinic. Data were collected from questionnaires and sleep studies reports of 395 children. A comparison between two screening tools for paediatric obstructive sleep apnea - a six-item (parent-response) and an eight-item IF-SLEEPY/IM-SLEEPY scales - was performed. The results showed that 42% of the children (n = 164) were diagnosed with obstructive sleep apnea. The six-item scale (score ≥3) exhibited a sensitivity of 17% and a specificity of 95% for diagnosing obstructive sleep apnea. The eight-item IF-SLEEPY scale displayed 82% sensitivity and 28% specificity. The IM-SLEEPY scale exhibited 79% sensitivity and 32% specificity. In children ≥7 years old, the IF-SLEEPY (parent-response) had a sensitivity of 82% and specificity of 28% compared with the child-response (66% and 37%, respectively). Logistic regression analysis revealed that age (odds ratio = 0.78), IF-SLEEPY/IM-SLEEPY score ≥3 (odds ratio = 1.78) and a score ≥2.72 on the six-item scale (odds ratio = 4.54) were predictors of obstructive sleep apnea. This study suggests that the eight-item scale is a better screening tool for paediatric obstructive sleep apnea, with a higher sensitivity and simple yes/no responses that are easy to complete and to score., (© 2017 European Sleep Research Society.)

SLE is a complex autoimmune disease that results from the interplay of genetics, epigenetics and environmental exposures. DNA methylation is an epigenetic mechanism that regulates gene expression and tissue differentiation. Among all the epigenetic modifications, DNA methylation perturbations have been the most widely studied in SLE. It mediates processes relevant to SLE, including lymphocyte development, X-chromosome inactivation and the suppression of endogenous retroviruses. The establishment of most DNA methylation marks occurs in utero; however, a small percentage of epigenetic marks are dynamic and can change throughout a person's lifetime and in relation to exposures. In this review, we discuss the current understanding of the biology of DNA methylation and its regulators, the measurement and interpretation of methylation marks, the effects of genetics on DNA methylation and the role of environmental exposures with relevance to SLE. We also summarise research findings associated with SLE disease risk and heterogeneity. The robust finding of hypomethylation of interferon-responsive genes in patients with SLE and new associations beyond interferon-responsive genes such as cell-specific methylation abnormalities are described. We also discuss methylation changes associated with lupus nephritis, autoantibody status and disease activity. Lastly, we explore future research directions, emphasising the need for longitudinal studies, cell tissue and context-specific profiling, as well as integrative approaches. With new technologies, DNA methylation perturbations could be targeted and edited, offering novel therapeutic approaches., Competing Interests: Competing interests: None declared.

Objective: Parasomnias are common in childhood but there is no established treatment for parasomnias. The aim of this study was to (1) report on the outcome of using L-tryptophan to manage parasomnias in children and (2) examine sleep architecture and subjective psychological/sleep symptoms in children with parasomnia., Method: A retrospective analysis was conducted of charts of children (3-18 years old) who underwent polysomnographic testing and were diagnosed with primary parasomnia. Study patients were either prescribed L-tryptophan (daily dose range: 500-4500 mg, mean dose of 2400 mg) to manage their parasomnias or administered no treatment whereby parents/guardians declined treatment. Questionnaires assessing sleep and psychosocial symptoms were administered at the initial clinical consultation and a follow-up parasomnia outcome questionnaire was administered over the phone to parents/guardians., Results: One hundred and sixty-five children (106 boys, 59 girls) received a sleep diagnosis of primary parasomnia. A significantly (p < 0.001) higher proportion (84%) of children taking L-tryptophan experienced improvements in their parasomnia symptoms compared with those (47%) who chose not to use L-tryptophan. Polysomnography revealed that children with parasomnias had an altered sleep architecture based on age-related normative values. Children with a diagnosis of parasomnia were also subjectively more fatigued and endorsed more depressive symptoms., Conclusions: This study finds that parasomnias in children are not benign and that treatment with L-tryptophan provides a favorable outcome. Children diagnosed with parasomnia had altered sleep architecture, were more fatigued, and endorsed depressive symptoms. This study supports the need to diagnose and treat parasomnias in children.

Objective: African Americans, East Asians, and Hispanics with systemic lupus erythematous (SLE) are more likely to develop lupus nephritis (LN) than are SLE patients of European descent. The etiology of this difference is not clear, and this study was undertaken to investigate how genetic variants might explain this effect., Methods: In this cross-sectional study, 1244 SLE patients from multiethnic case collections were genotyped for 817,810 single-nucleotide polymorphisms (SNPs) across the genome. Continental genetic ancestry was estimated utilizing the program ADMIXTURE. Gene-based testing and pathway analysis was performed within each ethnic group and meta-analyzed across ethnicities. We also performed candidate SNP association tests with SNPs previously established as risk alleles for SLE, LN, and chronic kidney disease (CKD). Association testing and logistic regression models were performed with LN as the outcome, adjusted for continental ancestries, sex, disease duration, and age., Results: We studied 255 North European, 263 South European, 238 Hispanic, 224 African American and 264 East Asian SLE patients, of whom 606 had LN (48.7%). In genome-wide gene-based and candidate SNP analyses, we found distinct genes, pathways and established risk SNPs associated with LN for each ethnic group. Gene-based analyses showed significant associations between variation in ZNF546 (p = 1.0E-06), TRIM15 (p = 1.0E-06), and TRIMI0 (p = 1.0E-06) and LN among South Europeans, and TTC34 (p = 8.0E-06) was significantly associated with LN among Hispanics. The SNP rs8091180 in NFATC1 was associated with LN (OR 1.43, p = 3.3E-04) in the candidate SNP meta-analysis with the highest OR among African-Americans (OR 2.17, p = 0.0035)., Conclusion: Distinct genetic factors are associated with the risk of LN in SLE patients of different ethnicities. CKD risk alleles may play a role in the development of LN in addition to SLE-associated risk variants. These findings may further explain the clinical heterogeneity of LN risk and response to therapy observed between different ethnic groups., Competing Interests: The authors have declared that no competing interests exist.

The COPA syndrome is a monogenic, autoimmune lung and joint disorder first identified in 2015. This study sought to define the main pulmonary features of the COPA syndrome in an international cohort of patients, analyse patient responses to treatment and highlight when genetic testing should be considered. We established a cohort of subjects (N=14) with COPA syndrome seen at multiple centres including the University of California, San Francisco, CA, USA. All subjects had one of the previously established mutations in the COPA gene, and had clinically apparent lung disease and arthritis. We analysed cohort characteristics using descriptive statistics. All subjects manifested symptoms before the age of 12 years, had a family history of disease, and developed diffuse parenchymal lung disease and arthritis. 50% had diffuse alveolar haemorrhage. The most common pulmonary findings included cysts on chest computed tomography and evidence of follicular bronchiolitis on lung biopsy. All subjects were positive for anti-neutrophil cytoplasmic antibody, anti-nuclear antibody or both and 71% of subjects had rheumatoid factor positivity. All subjects received immunosuppressive therapy. COPA syndrome is an autoimmune disorder defined by diffuse parenchymal lung disease and arthritis. We analysed an international cohort of subjects with genetically confirmed COPA syndrome and found that common pulmonary features included cysts, follicular bronchiolitis and diffuse alveolar haemorrhage. Common extrapulmonary features included early age of onset, family history of disease, autoantibody positivity and arthritis. Longitudinal data demonstrated improvement on chest radiology but an overall decline in pulmonary function despite chronic treatment., Competing Interests: Conflict of interest: None declared

Purpose: To assess the relationship between eye position and anesthesia depth using the bispectral index (BIS) value, a parameter derived from electroencephalography data., Methods: We investigated the relationship between BIS value and eye position in 32 children who underwent surgery for epiblepharon under general anesthesia. BIS values were recorded continuously throughout the procedure (from induction to awakening). Eye positions were video-recorded and analyzed after surgery. The vertical position of each eye was scored according to its height in relation to the medial canthus. An eye position in which the upper eyelid covered one-third of the cornea was defined as a significant ocular elevation., Results: The BIS value correlated inversely with the end-tidal concentration of each anesthetic agent, whereas it correlated positively with the eye elevation score (eye position = 0.014 × BIS + 0.699, p = 0.011). The mean eye position score was significantly greater in patients whose BIS values were over 65. Eleven patients (34.4%) had significant ocular elevation; their mean concurrent BIS value was 61.6. Two of these patients had elevation during surgery and 9 had elevation during emergence from anesthesia., Conclusions: We found that high BIS values were correlated with low levels of anesthetic concentration and high eye position, suggesting that BIS monitoring may be useful for predicting eye position during anesthesia. Particular attention must be given to eye position during ophthalmic surgery. Anesthesia depth can be maintained by assuring that the BIS value remains below 65., Competing Interests: No potential conflict of interest relevant to this article was reported., (© 2018 The Korean Ophthalmological Society.)

Objective: To compare the percentage of patients at risk for obstructive sleep apnea (OSA) in open-angle glaucoma (OAG) versus controls using the STOP-Bang questionnaire., Methods: This study used a cross-sectional survey. Patients with OAG and controls completed the STOP-Bang questionnaire-a validated tool to identify patients at high risk for OSA. Patients were considered at risk if they scored 3 or more points or at high risk for moderate/severe OSA if they scored 5 or more out of the maximum 8 points. Demographic information, medical history, and previous diagnosis of OSA were recorded. Details regarding the patients' glaucoma were obtained from their medical records., Results: A total of 437 patients with OAG and 441 controls were included. The mean STOP-Bang score was 3.01 ± 1.3 for the glaucoma group and 3.03 ± 1.4 for the control group (p = 0.92). There was no significant difference between the percentage of subjects considered at risk for OSA (62.7% OAG vs 59.4% controls, p = 0.37) or at high risk for moderate/severe OSA (12.6% OAG vs 16.5% controls, p = 0.1). Significantly more patients in the control group had a previous diagnosis of OSA (p = 0.01). More patients with OAG reported feeling tired compared with controls (p = 0.003). A risk/high risk for OSA was not associated with glaucoma severity, progression, intraocular pressure control, or glaucoma type., Conclusions: Our results indicate that a risk or high risk for moderate/severe OSA as measured by the STOP-Bang questionnaire is not correlated with the presence or absence of glaucoma (regardless of the type), glaucoma severity, glaucoma progression, or IOP control., (Copyright © 2018 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.)

Primary angiitis of the central nervous system (PACNS) is rare but often included in the differential diagnosis for unusual or unexplained neurologic symptoms owing to its array of clinical manifestations. PACNS is not a single entity, but rather an umbrella term for distinct subtypes of disease affecting different parts of the CNS, different sized vessels, and with different histologic and pathologic findings. Although brain biopsy is considered the gold standard test, it is neither highly sensitive nor specific. One must always pursue a workup for mimics of PACNS. Treatment consists of prednisone monotherapy or combination therapy with prednisone and cyclophosphamide., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The cyclin-dependent kinase inhibitor, palbociclib has shown compelling efficacy in breast cancer patients. Several pre-clinical studies of glioblastoma (GBM) have also shown palbociclib to be efficacious. In this study, we investigated palbociclib in combination with radiation therapy (RT) for treating GBM. We tested palbociclib (with and without RT) on four patient-derived cell lines (PDCLs; RB1 retained; CDKN2A loss). We investigated the impact of therapy on the cell cycle and apoptosis using flow cytometry, in vitro . Balb/c nude mice were intracranially injected with the PDCL, GBM-L1 and treated orally with palbociclib (with and without RT). Overall survival was measured. Palbociclib treatment resulted in a significant increase in the percentage of cells in the G1 cell cycle phase. Apoptotic cell death, measured by Annexin V was induced. Palbociclib combined with RT acted synergistically with the significant impediment of colony formation. The oral treatment of mice with palbociclib did not show any significant survival advantage when compared to control mice, however when combined with RT, a survival advantage of 8 days was observed. Our results support the use of palbociclib as an adjuvant treatment to RT and warrant translation to the clinic., Competing Interests: The authors declare no conflict of interest.

Leucine-rich repeat kinase 2 (LRRK2) is a Ser/Thr kinase having mixed lineage kinase-like and GTPase domains, controlling neurite outgrowth and neuronal cell death. Evidence suggests that LRRK2 is involved in innate immune response signaling, but the underlying mechanism is yet unknown. A novel protein inhibitor of phosphatase 3B, RCAN1, is known to positively regulate inflammatory signaling through modulation of several intracellular targets of interleukins in immune cells. In the present study, we report that LRRK2 phosphorylates RCAN1 (RCAN1-1S) and is markedly up-regulated during interleukin-1β (IL-1β) treatment. During IL-1β treatment, LRRK2-mediated phosphorylation of RCAN1 promoted the formation of protein complexes, including that between Tollip and RCAN1. LRRK2 decreased binding between Tollip and IRAK1, which was accompanied by increased formation of the IRAK1-TRAF6 complex. TAK1 activity was significantly enhanced by LRRK2. Furthermore, LRRK2 enhanced transcriptional activity of NF-κB and cytokine IL-8 production. These findings suggest that LRRK2 might be important in positively modulating IL-1β-mediated signaling through selective phosphorylation of RCAN1.

Objective: Previous studies have shown that differential DNA methylation is associated with SLE susceptibility. How DNA methylation affects the clinical heterogeneity of SLE has not been fully defined. We conducted this study to identify differentially methylated CpG sites associated with nephritis among women with SLE., Methods: The methylation status of 428 229 CpG sites across the genome was characterised for peripheral blood cells from 322 women of European descent with SLE, 80 of whom had lupus nephritis, using the Illumina HumanMethylation450 BeadChip. Multivariable linear regression adjusting for population substructure and leucocyte cell proportions was used to identify differentially methylated sites associated with lupus nephritis. The influence of genetic variation on methylation status was investigated using data from a genome-wide association study of SLE. Pathway analyses were used to identify biological processes associated with lupus nephritis., Results: We identified differential methylation of 19 sites in 18 genomic regions that was associated with nephritis among patients with SLE (false discovery rate q<0.05). Associations for four sites in HIF3A , IFI44 and PRR4 were replicated when examining methylation data derived from CD4+ T cells collected from an independent set of patients with SLE. These associations were not driven by genetic variation within or around the genomic regions. In addition, genes associated with lupus nephritis in a prior genome-wide association study were not differentially methylated in this epigenome-wide study. Pathway analysis indicated that biological processes involving type 1 interferon responses and the development of the immune system were associated with nephritis in patients with SLE., Conclusions: Differential methylation of genes regulating the response to tissue hypoxia and interferon-mediated signalling is associated with lupus nephritis among women with SLE. These findings have not been identified in genetic studies of lupus nephritis, suggesting that epigenome-wide association studies can help identify the genomic differences that underlie the clinical heterogeneity of SLE., Competing Interests: Conflicts of Interest: None declared.

Purpose of Review: We review select studies of newly discovered rare variants in autoimmune diseases with a focus on newly described monogenic disorders, rheumatoid arthritis, and systemic lupus erythematosus., Recent Findings: Two new monogenic syndromes of inflammatory arthritis were discovered using whole exome sequencing: the coatomer subunit alpha syndrome because of rare mutations in coatomer subunit alpha and haploinsufficiency of A20 resulting from rare mutations in TNFAIP3. Targeted exon sequencing identified rare variants in IL2RA and IL2RB associated with rheumatoid arthritis. Rare variants in TREX1 and other genes associated with monogenic interferonopathies are also associated with systemic lupus erythematosus., Summary: Rare genetic variants contribute to the heritability of autoimmunity and provide key insight into both novel and previously implicated immunological pathways that are disrupted in autoimmune diseases.

Our laboratory has demonstrated that bone morphogenetic protein 13 prevented the effects of annular injury in an ovine model, maintaining intervertebral disc height, cell numbers and increasing extracellular matrix production compared to degenerated controls. The present study sought to examine the molecular effects of bone morphogenetic protein 13 on human degenerated disc cells and localize its expression in both human degenerate and scoliotic disc tissue. Effect of bone morphogenetic protein 13 on human derived nucleus pulposus, annulus fibrosus and endplate cells cultured in alginate beads was evaluated by changes in proteoglycan and collagen content. Migratory potential of disc cells towards bone morphogenetic protein 13 was also examined. Bone morphogenetic protein 13 induced significant proteoglycan accumulation in nucleus (18%), annulus (21%) and endplate (23%) cells cultured in alginate beads (p<0.05) compared to controls. Further bone morphogenetic protein 13 increased collagen I and II protein expression in nucleus and endplate cells. Nucleus cells displayed a significant chemotactic response towards bone morphogenetic protein 13. The endogenous expression of bone morphogenetic protein 13 in degenerate disc tissue was not different to scoliotic disc. Bone morphogenetic protein 13 has the potential to enhance extracellular matrix accumulation and induce cell migration in certain disc cells., (© 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Purpose: Opioid treatment of non-malignant chronic pain can result in hypoxemia, hypercarbia, and central sleep apnea. The aim of this study was to determine the initial efficacy of auto servo-ventilation (ASV) and after 3 months of home use., Methods: This prospective multicenter interventional study recruited chronic pain patients prescribed ≥100 morphine equivalents for at least 4 months., Participants: Following full-night polysomnography (PSG) to confirm the presence of sleep-disordered breathing, patients were randomized to three additional full-night-attended PSGs with continuous positive airway pressure (CPAP), ASV, and servo-ventilation with an initial mandatory pressure support of 6 cm H2O (ASV manual PSmin 6). Following the PSGs, patients were sent home with EncoreAnywhere and ASV with or without mandatory pressure support., Results: Based on the initial PSG studies, CPAP improved but did not normalize the apnea-hypopnea index (AHI), central apnea index (CAI), or hypopnea index (HI), as all remained elevated. Clinically significant reductions were noted after just one night of ASV and ASV manual (PSmin 6). After 3 months of ASV home use, the AHI, CAI, and obstructive apnea index (OAI) were significantly reduced when compared to baseline diagnostic levels and even when compared to respiratory disturbance indices with CPAP treatment., Conclusions: Initial and home use of ASV for 3 months resulted in significantly lower AHI, CAI, and OAI. This reduction attests to the efficacy of ASV treatment in chronic pain patients on high doses of opioids.

Objective: The purpose of this study was to test PENAO, a promising new organoarsenical that is in phase 1 testing in patients with solid tumours, on a range of ovarian cancer cell lines with different histotypes, and to understand the molecular basis of drug resistance exhibited by the endometrioid ovarian cancer cell line, SKOV-3., Methods: Proliferation arrest and cell death induced by PENAO in serous (OVCAR-3), endometrioid (SKOV-3, TOV112D), clear cell (TOV21G) and mucinous (EFO27) ovarian cancer cells in culture, and anti-tumour efficacy in a murine model of SKOV-3 and OVCAR-3 tumours, were measured. Cells were analysed for cell cycle arrest, cell death mechanisms, reactive oxygen species production, mitochondrial depolarisation, oxygen consumption and acid production., Results: PENAO demonstrated promising anti-proliferative activity on the most common (serous, endometrioid) as well as on rare (clear cell, mucinous) subtypes of ovarian cancer cell lines. No cross-resistance with platinum-based drugs was evident. Endometrioid SKOV-3 cells were, however, shown to be resistant to PENAO in vitro and in a xenograft mouse model. This resistance was due to an ability to cope with PENAO-induced oxidative stress, notably through heme oxygenase-1 induction, and a shift in metabolism towards glycolysis. The adaptive glycolytic shift in SKOV-3 was targeted using a mTORC1 inhibitor in combination with PENAO. This strategy was successful with the two drugs acting synergistically to inhibit cell proliferation and to induce cell death via apoptosis and autophagy., Conclusion: Mitochondria/mTOR dual-targeting therapy may constitute a new approach for the treatment of recurrent/resistant forms of epithelial ovarian cancer., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Systemic lupus erythematosus (SLE) is characterized by the development of autoantibodies associated with specific clinical manifestations. Previous studies have shown an association between differential DNA methylation and SLE susceptibility, but have not investigated SLE-related autoantibodies. Our goal was to determine whether DNA methylation is associated with production of clinically relevant SLE-related autoantibodies, with an emphasis on the anti-dsDNA autoantibody. In this study, we characterized the methylation status of 467,314 CpG sites in 326 women with SLE. Using a discovery and replication study design, we identified and replicated significant associations between anti-dsDNA autoantibody production and the methylation status of 16 CpG sites (pdiscovery<1.07E-07 and preplication<0.0029) in 11 genes. Associations were further investigated using multivariable regression to adjust for estimated leukocyte cell proportions and population substructure. The adjusted mean DNA methylation difference between anti-dsDNA positive and negative cases ranged from 1.2% to 19%, and the adjusted odds ratio for anti-dsDNA autoantibody production comparing the lowest and highest methylation tertiles ranged from 6.8 to 18.2. Differential methylation for these CpG sites was also associated with anti-SSA, anti-Sm, and anti-RNP autoantibody production. Overall, associated CpG sites were hypomethylated in autoantibody positive compared to autoantibody negative cases. Differential methylation of CpG sites within the major histocompatibility region was not strongly associated with autoantibody production. Genes with differentially methylated CpG sites represent multiple biologic pathways, and have not been associated with autoantibody production in genetic association studies. In conclusion, hypomethylation of CpG sites within genes from different pathways is associated with anti-dsDNA, anti-SSA, anti-Sm, and anti-RNP production in SLE, and these associations are not explained by genetic variation. Thus, studies of epigenetic mechanisms such as DNA methylation represent a complementary method to genetic association studies to identify biologic pathways that may contribute to the clinical heterogeneity of autoimmune diseases.

Background: Glioblastoma (GBM) is the most common and malignant primary brain tumor. In contrast to some other tumor types, aberrant glucose metabolism is an important component of GBM growth and chemoresistance. Recent studies of human orthotopic GBM in mice and in situ demonstrated GBM cells rely on both glycolysis and mitochondrial oxidation for glucose catabolism. These observations suggest that the homeostasis of energy metabolism of GBM cells might be further disturbed by dual-inhibition of glucose metabolism. The present study aimed to evaluate the efficacy and the mechanisms of dual-targeting therapy in GBM cells., Methods: Representative GBM cells (immortalized GBM cell lines and patient-derived GBM cells) and non-cancerous cells were treated with 4-(N-(S-penicillaminylacetyl)amino) phenylarsonous acid (PENAO), an in-house designed novel arsenic-based mitochondrial toxin, in combination with dichloroacetate (DCA), a pyruvate dehydrogenase kinase inhibitor. The efficacy of this combinatorial therapy was evaluated by MTS assay, clonogenic surviving assay and apoptotic assays. The underlying mechanisms of this dual-targeting treatment were unraveled by using mitochondrial membrane potential measurements, cytosol/mitochondrial ROS detection, western blotting, extracellular flux assay and mass spectrometry., Results: As monotherapies, both PENAO and DCA induced proliferation arrest in a panel of GBM cell lines and primary isolates. PENAO inhibited oxygen consumption, induced oxidative stress and depolarized mitochondrial membrane potential, which in turn activated mitochondria-mediated apoptosis. By combining DCA with PENAO, the two drugs worked synergistically to inhibit cell proliferation (but had no significant effect on non-cancerous cells), impair the clonogenicity, and induce mitochondria-mediated apoptosis. An oxidative stress of mitochondrial origin takes a prominent place in the mechanism by which the combination of PENAO and DCA induces cell death. Additionally, PENAO-induced oxidative damage was enhanced by DCA through glycolytic inhibition which in turn diminished acid production induced by PENAO. Moreover, DCA treatment also led to an alteration in the multidrug resistance (MDR) phenotype of GBM cells, thereby leading to an increased cytosolic accumulation of PENAO., Conclusions: The findings of this study shed a new light with respect to the dual-targeting of glucose metabolism in GBM cells and the innovative combination of PENAO and DCA shows promise in expanding GBM therapies.

Prader-Willi syndrome (PWS) is a genetic disorder characterized by short stature, mental retardation, hypotonia, functionally deficient gonads, and uncontrolled appetite leading to extreme obesity at an early age. Patients with this condition require multidisciplinary medical care, which facilitates a significant improvement in quality of life. PWS is the first human disorder to be attributed to genomic imprinting. Prevalence varies in the literature, ranging from 1 in 8,000 in the Swedish population to 1 in 54,000 in the United Kingdom. Rarely, the genetic mechanism responsible for Prader-Willi syndrome can be inherited. We report a highly unique case of three siblings who share this condition. This report describes a case of two brothers and one half sister with PWS. All three siblings have sleep-related complaints. The sister died at the age of 24 years in her sleep, with the cause of death reported as obstructive sleep apnea. The outcome was positive in both of the brothers' cases as a result of professional medical care and specific tailored recommendations implemented by their mother. A review of the relevant literature vis-à-vis sleep and PWS is provided.

The ocular and systemic abnormalities of nonsyndromic craniosynostosis are often considered to be less severe than those of syndromic craniosynostosis and are less well described. The purpose of this article was to describe the frequency and nature of ophthalmic abnormalities in children treated for nonsyndromic craniosynostosis by expansion cranioplasty. A retrospective review identified 88 consecutive children with nonsyndromic craniosynostosis who underwent expansion cranioplasty with distraction osteogenesis. Assessment of presence and type of strabismus, refractive error, and amblyopia before and 6 months after surgery was recorded. Children with a mean age of 24.4 months were treated for nonsyndromic craniosynostosis (27 with coronal and 61 with sagittal and/or lambdoid). One-fourth of the patients had a fixation preference. Significant refractive errors were found in 45 (51%) of the 88 patients: hyperopia in 27%, myopia in 5%, and astigmatism in 35%. Anisometropia was present in 20%. Of the 85 patients who completed orthoptic examination, 48 (56%) had strabismus: exodeviation in 26%, esodeviation in 14%, and vertical deviation in 5%. Fourteen patients (16%) had abnormal head posture. Significant refractive error and strabismus were more likely to occur in cases with coronal synostosis. The procedures used for cranial vault expansion improved the abnormal head posture but did not affect the refractive error or ocular misalignment. Of children with nonsyndromic craniosynostosis who need neurosurgical correction, more than half were found to have significant refractive error and strabismus. Our findings support the importance of ophthalmic evaluation in these children.

Background: Pediatric obstructive sleep apnea (OSA) is a prevalent but under-diagnosed disease. The importance of screening for OSA has been emphasized in the recently published guidelines for the diagnosis and management of childhood OSA. Several pediatric OSA questionnaires are available, but are complicated to use or not sensitive enough for screening., Methods: In this study we developed an 8-item (IF SLEEPY) screening tool for pediatric OSA. One hundred and fifty children referred for evaluation at a pediatric sleep clinic and their parents completed the questionnaire and had a polysomnography. Two further questionnaires were developed: I SLEEPY and I'M SLEEPY versions. The questionnaires' scores were compared to the apnea hypopnea index (AHI) and the validity of each questionnaire was evaluated., Results: The I'M SLEEPY version was found to have the highest sensitivity (82%) and a modest specificity (50%) for OSA diagnosis., Conclusion: I'M SLEEPY is a sensitive and easy-to-use screening tool for pediatric OSA. It is intended to be used by the primary physician in every suspected case of OSA. Larger studies are needed in the primary care setting for the validation of this tool., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Lupus nephritis is a manifestation of SLE resulting from glomerular immune complex deposition and inflammation. Lupus nephritis demonstrates familial aggregation and accounts for significant morbidity and mortality. We completed a meta-analysis of three genome-wide association studies of SLE to identify lupus nephritis-predisposing loci. Through genotyping and imputation, >1.6 million markers were assessed in 2000 unrelated women of European descent with SLE (588 patients with lupus nephritis and 1412 patients with lupus without nephritis). Tests of association were computed using logistic regression adjusting for population substructure. The strongest evidence for association was observed outside the MHC and included markers localized to 4q11-q13 (PDGFRA, GSX2; P=4.5×10(-7)), 16p12 (SLC5A11; P=5.1×10(-7)), 6p22 (ID4; P=7.4×10(-7)), and 8q24.12 (HAS2, SNTB1; P=1.1×10(-6)). Both HLA-DR2 and HLA-DR3, two well established lupus susceptibility loci, showed evidence of association with lupus nephritis (P=0.06 and P=3.7×10(-5), respectively). Within the class I region, rs9263871 (C6orf15-HCG22) had the strongest evidence of association with lupus nephritis independent of HLA-DR2 and HLA-DR3 (P=8.5×10(-6)). Consistent with a functional role in lupus nephritis, intra-renal mRNA levels of PDGFRA and associated pathway members showed significant enrichment in patients with lupus nephritis (n=32) compared with controls (n=15). Results from this large-scale genome-wide investigation of lupus nephritis provide evidence of multiple biologically relevant lupus nephritis susceptibility loci., (Copyright © 2014 by the American Society of Nephrology.)

Purpose: To evaluate the impact of myopic keratorefractive surgery on ocular alignment., Methods: This prospective study included 194 eyes of 97 myopic patients undergoing laser refractive surgery. All patients received a complete ophthalmic examination with particular attention to ocular alignment before and 3 months after surgery., Results: Patients with a mean age of 26.6 years and a mean refractive error of -4.83 diopters (D) myopia were treated. Asymptomatic ocular misalignment was present preoperatively in 46 (47%) patients: a small-angle heterophoria (1-8 prism diopters, PD) in 36%; and a large-angle heterophoria (>8 PD)/heterotropia in 11%. Postoperatively, the change in angles of 10 PD or greater occurred in 3% for distance and 6% for near fixation: in 7% of the patients with orthophoria, in 3% of those with a small-angle heterophoria, and in 18% of those with a large-angle heterophoria/heterotropia. No patient developed diplopia. The preoperative magnitude of myopia or postoperative refractive status was not related to the change in ocular alignment. The higher anisometropia was associated with a decrease in deviation (P=0.041 for distance and P=0.002 for near fixation), whereas the further near point of convergence tended to be related with an increase in near deviation (P=0.055)., Conclusions: Myopic refractive surgery may cause a change in ocular alignment, especially in cases with a large-angle heterophoria/heterotropia. There is also a chance of improvement of misalignment in patients with anisometropia.

Pain and sleep share a bidirectional relationship, with each influencing the other. Several excellent reviews have explored this relationship. In this article, we revisit the evidence and explore existing research on this complex inter-relationship. The primary focus of the article is on the pharmacological treatment of chronic non-malignant pain and the main purpose is to review the effect of various pharmacological agents used in the management of chronic pain on sleep. This has not been comprehensively done before. We explore the clinical use of these agents, their impact on sleep architecture and sleep physiology, the mechanism of action on sleep parameters and sleep disorders associated with these agents. Pharmacological classes reviewed include antidepressants, opioid analgesics, anti-epileptics, cannabinoids and non-steroidal anti-inflammatory agents, drugs most commonly used to manage chronic pain. The objective is to help health professionals gain better insight into the complex effect that commonly used analgesics have on an individual's sleep and how this could impact on the effectiveness of the drug as an analgesic. We conclude that antidepressants have both positive and negative effects on sleep, so do opioids, but in the latter case the evidence shifts towards the counterproductive side. Some anticonvulsants are sleep sparing and non-steroidal anti-inflammatory drugs (NSAIDs) are sleep neutral. Cannabinoids remain an underexplored and researched group.

Objective: HIV-associated neurocognitive disorders (HANDs) remain prevalent in patients who receive HAART and may be associated with cumulative exposure to antiretroviral medications and other factors. We proposed that chronic toxic effects of antiretroviral drugs could contribute to cerebral small vessel disease (CSVD), which might be one of the key underpinnings of HAND., Design: Clinicopathological cross-sectional study of HIV-infected adults in the California NeuroAIDS Tissue Network., Methods: We employed multivariable logistic regression methods to determine associations between HAART exposure (protease inhibitor-based, nonprotease inhibitor-based, or no HAART) and CSVD occurrence (standard histopathology: moderate/severe, mild, or absent). We also associated HAND (relative to normal cognition) with CSVD, HIV-related neuropathologic changes, older age at death (≥50 years), sex, or hepatitis C virus infection., Results: We found that both mild and moderate/severe CSVD were associated with protease inhibitor-based HAART exposure after adjusting for diabetes mellitus [odds ratio (OR) 2.8 (95% confidence interval, CI 1.03-7.9) and 2.6 (95% CI 1.03-6.7), respectively, n = 134]. Moderate/severe CSVD was associated with diabetes after adjusting for HAART exposure [OR 7.4 (95% CI 1.6-70.7), n = 134]. Notably, HAND was associated with mild CSVD [OR 4.8 (95% CI 1.1-21.2), n = 63], which remained statistically significant after adjusting for vessel mineralization, HIV encephalitis, microglial nodular lesions, white matter lesions, or older age., Conclusion: Protease inhibitor-based HAART exposure may increase the risk of CSVD and thereby neurocognitive impairment in HIV-infected adults. Apart from the possible direct toxicity to cerebral small vessels, protease inhibitor-based HAART may contribute indirectly to CSVD by inducing metabolic abnormalities.

Purpose: This study aimed to investigate the effect of pirfenidone on the IL-1β-induced hyaluronic acid (HA) increase in orbital fibroblasts from patients with thyroid-associated ophthalmopathy (TAO)., Methods: Primary cultured orbital fibroblasts were obtained from patients with TAO, and the excreted levels of HA from IL-1β-treated cells with or without pirfenidone were measured. The effect of pirfenidone on IL-1β-induced hyaluronic acid synthase (HAS) expression was evaluated. The relevance of the mitogen-activated protein kinase (MAPK)-mediated signaling pathway in IL-1β-induced HAS expression was assessed using specific inhibitors to p38, extracellular signal-regulated kinase (ERK), or c-Jun N-terminal kinase (JNK). The phosphorylation level of each MAPK in IL-1β-treated cells with or without pirfenidone and the level of AP-1 DNA binding were measured. The inhibitory potency of pirfenidone on HA production was evaluated using dexamethasone as a reference agent., Results: Pirfenidone strongly attenuated the IL-1β-induced HA release in a dose-dependent manner. The IL-1β-induced HAS expression was decreased significantly following cotreatment with pirfenidone at the mRNA and protein levels. The production of mRNAs was halted by cotreatment with inhibitors of ERK and p38, but not by inhibitors of JNK. The IL-1β-induced ERK and p38 phosphorylation, and AP-1 DNA binding were attenuated in the presence of pirfenidone. Pirfenidone showed greater potency than dexamethasone in inhibiting increases in IL-1β-induced HA., Conclusions: Pirfenidone attenuates the IL-1β-induced HA production in orbital fibroblasts from patients with TAO, at least in part, through suppression of the MAPK-mediated HAS expression. These results support the potential use of pirfenidone for treatment of patients with TAO.

Objective: To describe the relationship between sleep architecture and behavioral measures in unmedicated children and adolescents with Tourette syndrome (TS), attention-deficit hyperactivity disorder (ADHD), TS and comorbid ADHD (TS + ADHD), and healthy controls. The study also set out to examine differences in sleep architecture with each diagnosis., Method: A cross-sectional, 2-night consecutive polysomnographic sleep study was conducted in 90 children. All participants were matched for age, gender, and level of intelligence., Results: Scores on the Child Behavior Checklist delinquency measure were modestly but significantly correlated with the number of movements during REM sleep (r = .36, p = .003). Significant correlations were also noted among the number of total arousals and arousals from slow wave sleep (SWS), and scores on the measures of conduct disorder, hyperactivity/immaturity, and restless/disorganized behaviors. There were a few significant differences in sleep architecture among the diagnostic groups. The ADHD-only group exhibited a significantly higher number of total arousals (p < .01) and arousals from SWS (p < .01) compared with the other three study groups., Discussion: Our findings indicate that children with TS and/or ADHD and who have more arousals from sleep are significantly more likely to have issues with conduct disorder, hyperactivity/immaturity, and restless/disorganized behavior. It was also noted that having ADHD, alone or comorbid with TS, is associated with a significantly greater number of movements during both non-REM and REM sleep. This study underscores the compelling need for the diagnosis and treatment of any sleep disorders in children with TS and/or ADHD so as to facilitate better management of problem behaviors.

Objective: Pediatric obstructive sleep apnea (OSA) is a prevalent but under-diagnosed disease. The importance of screening for OSA in every child has been recently re-emphasized by the American Academy of Pediatrics Guidelines. Although several screening questionnaires are available for pediatric OSA, they are either complicated to use or not sensitive enough, and therefore OSA is seldom screened in primary care settings. Here, we validated a previously developed short (6-item) hierarchically-based screening questionnaire tool for pediatric OSA., Methods: Parents of 85 children referred for a sleep study at a pediatric community-based sleep clinic completed the questionnaire and their children underwent an overnight PSG. Receiver operator curve analyses and other predictive scales were assessed., Results: The 6-item questionnaire exhibited favorable sensitivity and fair specificity for diagnosis of OSA, which varied depending on the apnea-hypopnea index used for OSA definition., Conclusions: A 6-item questionnaire is a sensitive and easy-to-use screening tool for pediatric OSA in a pediatric sleep clinic setting., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Protein tyrosine phosphatase non-receptor type 22 (PTPN22) is a negative regulator of T-cell activation associated with several autoimmune diseases, including systemic lupus erythematosus (SLE). Missense rs2476601 is associated with SLE in individuals with European ancestry. Since the rs2476601 risk allele frequency differs dramatically across ethnicities, we assessed robustness of PTPN22 association with SLE and its clinical sub-phenotypes across four ethnically diverse populations. Ten SNPs were genotyped in 8220 SLE cases and 7369 controls from in European-Americans (EA), African-Americans (AA), Asians (AS), and Hispanics (HS). We performed imputation-based association followed by conditional analysis to identify independent associations. Significantly associated SNPs were tested for association with SLE clinical sub-phenotypes, including autoantibody profiles. Multiple testing was accounted for by using false discovery rate. We successfully imputed and tested allelic association for 107 SNPs within the PTPN22 region and detected evidence of ethnic-specific associations from EA and HS. In EA, the strongest association was at rs2476601 (P = 4.7 × 10(-9), OR = 1.40 (95% CI = 1.25-1.56)). Independent association with rs1217414 was also observed in EA, and both SNPs are correlated with increased European ancestry. For HS imputed intronic SNP, rs3765598, predicted to be a cis-eQTL, was associated (P = 0.007, OR = 0.79 and 95% CI = 0.67-0.94). No significant associations were observed in AA or AS. Case-only analysis using lupus-related clinical criteria revealed differences between EA SLE patients positive for moderate to high titers of IgG anti-cardiolipin (aCL IgG >20) versus negative aCL IgG at rs2476601 (P = 0.012, OR = 1.65). Association was reinforced when these cases were compared to controls (P = 2.7 × 10(-5), OR = 2.11). Our results validate that rs2476601 is the most significantly associated SNP in individuals with European ancestry. Additionally, rs1217414 and rs3765598 may be associated with SLE. Further studies are required to confirm the involvement of rs2476601 with aCL IgG.

Background: To assess the presence and extent of photophobia in children with intermittent exotropia (X[T]) using the contrast sensitivity test., Methods: Fifty-eight children with X(T) and 34 normal controls were studied with the functional acuity contrast test. Each participant viewed the stimuli of contrast monocularly and binocularly under photopic and mesopic conditions, performed with and without glare. Photophobia was defined as a reduction of contrast sensitivity caused by glare light. We compared the photophobia of children with X(T) to that of normal controls, and to the photophobia 3 months after muscle surgery., Results: With stimuli of glare, the contrast sensitivity of children with X(T) was suppressed at intermediate spatial frequencies under mesopic condition (p = 0.006 for 6 cycles per degree [cpd], p = 0.027 for 12 cpd), whereas that of normal controls showed no difference. It occurred when X(T) patients viewed targets binocularly, and significantly improved after strabismus surgery (p = 0.003 at 6 cpd). The measured photophobia of X(T) was strongly correlated to the photophobia symptoms reported by parents (p = 0.002)., Conclusions: The mesopic contrast sensitivity with glare can represent the photophobia of children with X(T). Contrast sensitivity may be a useful measure for monitoring symptoms related to X(T).

The c-Src tyrosine kinase, Csk, physically interacts with the intracellular phosphatase Lyp (encoded by PTPN22) and can modify the activation state of downstream Src kinases, such as Lyn, in lymphocytes. We identified an association of CSK with systemic lupus erythematosus (SLE) and refined its location to the intronic polymorphism rs34933034 (odds ratio (OR) = 1.32; P = 1.04 × 10(-9)). The risk allele at this SNP is associated with increased CSK expression and augments inhibitory phosphorylation of Lyn. In carriers of the risk allele, there is increased B-cell receptor (BCR)-mediated activation of mature B cells, as well as higher concentrations of plasma immunoglobulin M (IgM), relative to individuals with the non-risk haplotype. Moreover, the fraction of transitional B cells is doubled in the cord blood of carriers of the risk allele, due to an expansion of late transitional cells in a stage targeted by selection mechanisms. This suggests that the Lyp-Csk complex increases susceptibility to lupus at multiple maturation and activation points in B cells.

Objective: African Americans, East Asians, and Hispanics with systemic lupus erythematosus (SLE) are more likely to develop renal disease than are SLE patients of European descent. This study was undertaken to investigate whether European genetic ancestry protects against the development of lupus nephritis, with the aim of exploring the genetic and socioeconomic factors that might explain this effect., Methods: This was a cross-sectional study of SLE patients from a multiethnic case collection. Participants were genotyped for 126 single-nucleotide polymorphisms (SNPs) informative for ancestry. A subset of participants was also genotyped for 80 SNPs in 14 candidate genes for renal disease in SLE. Logistic regression was used to test the association between European ancestry and renal disease. Analyses were adjusted for continental ancestries, socioeconomic status (SES), and candidate genes., Results: Participants (n = 1,906) had, on average, 62.4% European, 15.8% African, 11.5% East Asian, 6.5% Amerindian, and 3.8% South Asian ancestry. Among the participants, 656 (34%) had renal disease. A 10% increase in the proportion of European ancestry estimated in each participant was associated with a 15% reduction in the odds of having renal disease, after adjustment for disease duration and sex (odds ratio 0.85, 95% confidence interval 0.82-0.87; P = 1.9 × 10(-30) ). Adjustment for other genetic ancestries, measures of SES, or SNPs in the genes most associated with renal disease (IRF5 [rs4728142], BLK [rs2736340], STAT4 [rs3024912], and HLA-DRB1*0301 and DRB1*1501) did not substantively alter this relationship., Conclusion: European ancestry is protective against the development of renal disease in SLE, an effect that is independent of other genetic ancestries, candidate risk alleles, and socioeconomic factors., (Copyright © 2012 by the American College of Rheumatology.)

Objective: To examine the association of previously identified autoimmune disease susceptibility loci with granulomatosis with polyangiitis (Wegener's) (GPA), and to determine whether the genetic susceptibility profiles of other autoimmune diseases are associated with those of GPA., Methods: Genetic data from 2 cohorts were meta-analyzed. Genotypes for 168 previously identified single-nucleotide polymorphisms (SNPs) associated with susceptibility to different autoimmune diseases were ascertained in a total of 880 patients with GPA and 1,969 control subjects of European descent. Single-marker associations were identified using additive logistic regression models. Associations of multiple SNPs with GPA were assessed using genetic risk scores based on susceptibility loci for Crohn's disease, type 1 diabetes, systemic lupus erythematosus, rheumatoid arthritis (RA), celiac disease, and ulcerative colitis. Adjustment for population substructure was performed in all analyses, using ancestry-informative markers and principal components analysis., Results: Genetic polymorphisms in CTLA4 were significantly associated with GPA in the single-marker meta-analysis (odds ratio [OR] 0.79, 95% confidence interval [95% CI] 0.70-0.89, P = 9.8 × 10(-5) ). The genetic risk score for RA susceptibility markers was significantly associated with GPA (OR 1.05 per 1-unit increase in genetic risk score, 95% CI 1.02-1.08, P = 5.1 × 10(-5) )., Conclusion: RA and GPA may arise from a similar genetic predisposition. Aside from CTLA4, other loci previously found to be associated with common autoimmune diseases were not statistically significantly associated with GPA in this study., (Copyright © 2012 by the American College of Rheumatology.)

Purpose: To investigate the symptoms of attention deficit hyperactivity disorder (ADHD) as reported by parents in children with intermittent exotropia [X(T)] and to determine whether strabismus surgery for X(T) affects ADHD symptoms., Materials and Methods: Fifty-one consecutive children undergoing muscle surgery for X(T) were prospectively recruited. One parent of each child completed the ADHD rating scale IV (ADHD RS-IV) assessment consecutively before and one year after surgery. Patients whose preoperative scores were above the cut-off point, the 90th percentile based on a Korean sample, were regarded as demonstrating the ADHD trait. The impact of muscle surgery on ADHD symptoms was assessed by comparing the preoperative scores with the post-operative scores., Results: Eight (15.7%) of the 51 patients demonstrated the ADHD trait. ADHD RS-IV scores following strabismus surgery significantly decreased in patients with the ADHD trait (p=0.014), while they did not differ in patients without the ADHD trait. Seven (87.5%) of the 8 patients with the ADHD trait showed improvement in their ADHD RS-IV scores after surgery. There was no difference in surgical success rates between X(T) patients with and without the ADHD trait., Conclusion: The ADHD trait was relatively common in children with X(T), and the parent-reported symptoms of the children with the ADHD trait improved after strabismus surgery. These results suggest that childhood X(T) may be one contributing factor to ADHD- related symptoms.

Purpose: To report the long term results of bifocal treatment in nonrefractive accommodative esotropia and to analyze the changes of accommodative convergence to accommodation (AC/A) ratio., Methods: Sixteen patients treated with bifocal glasses for at least 5 years were evaluated retrospectively. Angle of deviation at near and distance, refractive error, and AC/A ratio by the lens gradient method were analyzed. The changes of AC/A ratios were also compared after dividing the patients according to continuation or cessation of bifocal therapy., Results: Six patients (38%; bifocal stop group, BSG) were able to stop using bifocal glasses at an average age of 10.8 years (range, 6.5 to 15.4 years) during their follow-up. However, the other ten patients (62%; bifocal continue group, BCG) had to continue using bifocal glasses until the final visit, which was 13.8 years on average (range, 11.3 to 18.5 years). The AC/A ratio decreased from time of bifocal prescription to the last visit in both groups, from 4.4 to 2.7 in the BSG and from 5.9 to 4.5 in the BCG. AC/A ratios were significantly higher (p = 0.03) in the BCG than that of the BSG from the beginning of bifocal treatment and this difference was persistent until the final visit (p = 0.03)., Conclusions: The AC/A ratio decreased with age in both groups but was significantly higher throughout the entire follow-up period in the BCG. AC/A ratio at bifocal prescription could be an important factor in predicting response to bifocal treatment.

Purpose: To determine whether changes in ocular alignment following general anesthesia, as measured by interpupillary distance, can be used as a predictor for surgical outcomes in children with intermittent exotropia., Methods: The authors obtained digital photographs of 40 children with exotropia and 20 children with epiblepharon (control group) before and immediately after induction of general anesthesia in the primary supine position. Differences in the anatomic interpupillary distance (aIPD) for each patient were measured and compared with the preoperative angles of deviation. They were also correlated with surgical outcomes on the first day and 1 year after surgery., Results: All 60 patients demonstrated an increase in aIPD following general anesthesia. The mean change in aIPD in patients with exotropia was similar to that in patients with epiblepharon (3.78% ± 2.53% and 3.15% ± 1.05%, respectively). In patients with exotropia, there was a significant positive linear correlation between the preoperative distance deviation (P) and the change in eye position (A): A = 0.362 P - 4.488, r(2) = 0.476 (P < .001). Five (71%) of seven patients whose changes were outside the 80% confidence interval for expected values had poor surgical outcomes on the first postoperative day and four had unsatisfactory results 1 year after surgery., Conclusions: Changes in aIPD following general anesthesia were strongly correlated with preoperative angle of deviation. Therefore, they may be a useful predictor of surgical outcomes in children with exotropia., (Copyright 2012, SLACK Incorporated.)

In spite of the well-known clustering of multiple autoimmune disorders in families, analyses of specific shared genes and polymorphisms between systemic lupus erythematosus (SLE) and other autoimmune diseases (ADs) have been limited. Therefore, we comprehensively tested autoimmune variants for association with SLE, aiming to identify pleiotropic genetic associations between these diseases. We compiled a list of 446 non-Major Histocompatibility Complex (MHC) variants identified in genome-wide association studies (GWAS) of populations of European ancestry across 17 ADs. We then tested these variants in our combined Caucasian SLE cohorts of 1,500 cases and 5,706 controls. We tested a subset of these polymorphisms in an independent Caucasian replication cohort of 2,085 SLE cases and 2,854 controls, allowing the computation of a meta-analysis between all cohorts. We have uncovered novel shared SLE loci that passed multiple comparisons adjustment, including the VTCN1 (rs12046117, P = 2.02×10(-06)) region. We observed that the loci shared among the most ADs include IL23R, OLIG3/TNFAIP3, and IL2RA. Given the lack of a universal autoimmune risk locus outside of the MHC and variable specificities for different diseases, our data suggests partial pleiotropy among ADs. Hierarchical clustering of ADs suggested that the most genetically related ADs appear to be type 1 diabetes with rheumatoid arthritis and Crohn's disease with ulcerative colitis. These findings support a relatively distinct genetic susceptibility for SLE. For many of the shared GWAS autoimmune loci, we found no evidence for association with SLE, including IL23R. Also, several established SLE loci are apparently not associated with other ADs, including the ITGAM-ITGAX and TNFSF4 regions. This study represents the most comprehensive evaluation of shared autoimmune loci to date, supports a relatively distinct non-MHC genetic susceptibility for SLE, provides further evidence for previously and newly identified shared genes in SLE, and highlights the value of studies of potentially pleiotropic genes in autoimmune diseases., Competing Interests: RRG is an employee of Genentech.