Multisite prospective study of perioperative pain management practices for anterior cruciate ligament reconstruction in adolescents: Society for Pediatric Anesthesia Improvement Network (SPAIN) Project Report.

Introduction: Although 200 000 adolescents undergo anterior cruciate ligament reconstruction (ACLR) surgery annually, no benchmarks for pediatric post-ACLR pain management exist. We created a multicenter, prospective, observational registry to describe pain practices, pain, and functional recovery after pediatric ACLR.

Methods: Participants (n=519; 12-17.

Comprehension by Caregivers and Adolescents of Clinical Trial Information Delivered via Multimedia Video Versus Conventional Practice: Nonrandomized Controlled Trial.

Background: Research participants often misunderstand the required elements of informed consent information, whether provided in written or oral format. Informed consent instruments with embedded evidence-based learning theory principles administered in multimedia electronic formats may improve comprehension and retention.

Objective: This study aims to determine whether study information comprehension and retention using an interactive multimedia video consent process was noninferior to comprehension and retention after an in-person face-to-face interaction with a conventional written consent document for caregivers and adolescents enrolled in a clinical trial.

Online patient portal use by caregivers in pediatric oncology: Are we widening sociodemographic disparities?

Background: Financial and regulatory incentives have encouraged and increased the availability of online patient portals that provide caregivers access to their child's electronic health records (EHR). Such access is believed to promote better engagement and outcomes of care. Little is known about the use of portals by caregivers of children with cancer.

The culture microenvironment of juvenile idiopathic arthritis synovial fibroblasts is favorable for endochondral bone formation through BMP4 and repressed by chondrocytes.

Background: We examined influences of conditioned media from chondrocytes (Ch) on juvenile idiopathic arthritis synovial fibroblasts (JFLS) and potential for JFLS to undergo endochondral bone formation (EBF).

Methods: Primary cells from three control fibroblast-like synoviocytes (CFLS) and three JFLS were cultured in Ch-conditioned media and compared with untreated fibroblast-like synoviocytes (FLS). RNA was analyzed by ClariomS microarray.

Juvenile idiopathic arthritis fibroblast-like synoviocytes influence chondrocytes to alter BMP antagonist expression demonstrating an interaction between the two prominent cell types involved in endochondral bone formation.

Background: To examine critical interactions between juvenile idiopathic arthritis synovial fibroblasts (JFLS) and chondrocytes (Ch), and their role in bony overgrowth seen in patients with juvenile idiopathic arthritis (JIA).

Methods: Control (CFLS) and JFLS were cultured in synoviocyte media containing recombinant BMP4. Ch were cultured in either CFLS or JFLS conditioned-media without stimulation.

Quantitative sensory testing in children with sickle cell disease: additional insights and future possibilities.

Quantitative sensory testing (QST) is used in a variety of pain disorders to characterize pain and predict prognosis and response to specific therapies. In this study, we aimed to confirm results in the literature documenting altered QST thresholds in sickle cell disease (SCD) and assess the test-retest reliability of results over time. Fifty-seven SCD and 60 control subjects aged 8-20 years underwent heat and cold detection and pain threshold testing using a Medoc TSAII.

Prior to extension, Transcriptomes of fibroblast-like Synoviocytes from extended and Polyarticular juvenile idiopathic arthritis are indistinguishable.

Background: Our intent was to identify differences between the transcriptome of fibroblast-like synoviocytes (FLS) in oligoarticular juvenile idiopathic arthritis (JIA) before extension when compared to persistent subtype of JIA, when the two are clinically indistinguishable. Additionally, we sought to determine if differences between the transcriptomes of FLS from extended-to-be and polyarticular course JIA could be detected. Our hypothesis was that intrinsic differences in the transcriptome of the FLS from extended-to-be JIA would distinguish them from persistent oligoarticular JIA, before the course is clinically apparent.

Epigenetic drug combination induces remission in mouse xenograft models of pediatric acute myeloid leukemia.

Aberrations in epigenetic modifications contribute to leukemogenesis in childhood acute myeloid leukemia (AML). We combined DNA hypomethylating agent azacitidine with histone deacetylase inhibitor panobinostat in preclinical models of childhood AML. Synergistic cytotoxic effect upon treatment with azacitidine and panobinostat with combination indices <1.

A cognitive approach for design of a multimedia informed consent video and website in pediatric research.

Objective: Poor participant comprehension of research procedures following the conventional face-to-face consent process for biomedical research is common. We describe the development of a multimedia informed consent video and website that incorporates cognitive strategies to enhance comprehension of study related material directed to parents and adolescents.

Materials And Methods: A multidisciplinary team was assembled for development of the video and website that included human subjects professionals; psychologist researchers; institutional video and web developers; bioinformaticians and programmers; and parent and adolescent stakeholders.

Identification of early gene expression changes in primary cultured neurons treated with topoisomerase I poisons.

Topoisomerase 1 (TOP1) poisons like camptothecin (CPT) are currently used in cancer chemotherapy but these compounds can have damaging, off-target effects on neurons leading to cognitive, sensory and motor deficits. To understand the molecular basis for the enhanced sensitivity of neurons to CPT, we examined the effects of compounds that inhibit TOP1-CPT, actinomycin D (ActD) and β-lapachone (β-Lap)-on primary cultured rat motor (MN) and cortical (CN) neurons as well as fibroblasts. Neuronal cells expressed higher levels of Top1 mRNA than fibroblasts but transcript levels are reduced in all cell types after treatment with CPT.

Polygenic inheritance of cryptorchidism susceptibility in the LE/orl rat.

Study Hypothesis: Susceptibility to inherited cryptorchidism in the LE/orl rat may be associated with genetic loci that influence developmental patterning of the gubernaculum by the fetal testis.

Study Finding: Cryptorchidism in the LE/orl rat is associated with a unique combination of homozygous minor alleles at multiple loci, and the encoded proteins are co-localized with androgen receptor (AR) and Leydig cells in fetal gubernaculum and testis, respectively.

What Is Known Already: Prior studies have shown aberrant perinatal gubernacular migration, muscle patterning defects and reduced fetal testicular testosterone in the LE/orl strain.

Use of mobile devices and the internet for multimedia informed consent delivery and data entry in a pediatric asthma trial: Study design and rationale.

Introduction: Phase III/IV clinical trials are expensive and time consuming and often suffer from poor enrollment and retention rates. Pediatric trials are particularly difficult because scheduling around the parent, participant and potentially other sibling schedules can be burdensome. We are evaluating using the internet and mobile devices to conduct the consent process and study visits in a streamlined pediatric asthma trial.

Complex genomic rearrangements at the PLP1 locus include triplication and quadruplication.

Inverted repeats (IRs) can facilitate structural variation as crucibles of genomic rearrangement. Complex duplication-inverted triplication-duplication (DUP-TRP/INV-DUP) rearrangements that contain breakpoint junctions within IRs have been recently associated with both MECP2 duplication syndrome (MIM#300260) and Pelizaeus-Merzbacher disease (PMD, MIM#312080). We investigated 17 unrelated PMD subjects with copy number gains at the PLP1 locus including triplication and quadruplication of specific genomic intervals-16/17 were found to have a DUP-TRP/INV-DUP rearrangement product.

Characterization of pediatric acute lymphoblastic leukemia survival patterns by age at diagnosis.

Age at diagnosis is a key prognostic factor in pediatric acute lymphoblastic leukemia (ALL) survivorship. However, literature providing adequate assessment of the survival variability by age at diagnosis is scarce. The aim of this study is to assess the impact of this prognostic factor in pediatric ALL survival.

Transcriptome profiling of spinal muscular atrophy motor neurons derived from mouse embryonic stem cells.

Proximal spinal muscular atrophy (SMA) is an early onset, autosomal recessive motor neuron disease caused by loss of or mutation in SMN1 (survival motor neuron 1). Despite understanding the genetic basis underlying this disease, it is still not known why motor neurons (MNs) are selectively affected by the loss of the ubiquitously expressed SMN protein. Using a mouse embryonic stem cell (mESC) model for severe SMA, the RNA transcript profiles (transcriptomes) between control and severe SMA (SMN2+/+;mSmn-/-) mESC-derived MNs were compared in this study using massively parallel RNA sequencing (RNA-Seq).

Cryptorchidism in the orl rat is associated with muscle patterning defects in the fetal gubernaculum and altered hormonal signaling.

Cryptorchidism, or undescended testis, is a common male genital anomaly of unclear etiology. Hormonal stimulation of the developing fetal gubernaculum by testicular androgens and insulin-like 3 (INSL3) is required for testicular descent. In studies of the orl fetal rat, one of several reported strains with inherited cryptorchidism, we studied hormone levels, gene expression in intact and hormone-stimulated gubernaculum, and imaging of the developing cremaster muscle facilitated by a tissue clearing protocol to further characterize development of the orl gubernaculum.

Identification of gene expression changes in postnatal rat foreskin after in utero anti-androgen exposure.

In utero human phthalate exposure has been associated with male reproductive disorders in epidemiological studies, but discovering relationships is hindered by the lack of identifying markers. This study identified gene expression changes following in utero dibutyl phthalate (DBP) and flutamide exposures in Sprague-Dawley rat foreskin. Dams were exposed to 100 or 500mg/kg/day dibutyl phthalate or 5mg/kg/day flutamide from gestational days 16-20.

The role of transforming growth factor β signaling in fibroblast-like synoviocytes from patients with oligoarticular juvenile idiopathic arthritis: dysregulation of transforming growth factor β signaling, including overexpression of bone morphogenetic protein 4, may lead to a chondrocyte phenotype and may contribute to bony hypertrophy.

Objective: This study was designed to investigate the pathogenic contributions of fibroblast-like synoviocytes (FLS) to juvenile idiopathic arthritis (JIA) by identifying pathways with dysregulated gene expression in FLS from patients with oligoarticular JIA.

Methods: FLS were derived from synovial fluid obtained by arthrocentesis from patients with JIA undergoing intraarticular steroid injections and from orthopedic control patients. Gene expression profiles of the JIA and control FLS were obtained using the Affymetrix platform, with application of Ingenuity Pathway Analysis and Gene Set Enrichment Analysis software to define gene sets in dysregulated pathways and networks of potential pathologic relevance in this disease.

Transcriptome analysis of the dihydrotestosterone-exposed fetal rat gubernaculum identifies common androgen and insulin-like 3 targets.

Androgens and insulin-like 3 (INSL3) are required for development of the fetal gubernaculum and testicular descent. Previous studies suggested that the INSL3-exposed fetal gubernacular transcriptome is enriched for genes involved in neural pathways. In the present study, we profiled the transcriptome of fetal gubernaculum explants exposed to dihydrotestosterone (DHT) and compared this response to that with INSL3.

Insulin-like 3 exposure of the fetal rat gubernaculum modulates expression of genes involved in neural pathways.

Insulin-like 3 (INSL3) signaling directs fetal gubernacular development and testis descent, but the actions of INSL3 in the gubernaculum are poorly understood. Using microarray gene expression profiling of fetal male rat gubernaculum explants exposed to 10 or 100 nM INSL3, significant changes in expression were identified for approximately 900 genes. Several of the genes showing the largest inductions regulate neuronal development or activity, including Pnoc (34-fold), Nptx2 (9-fold), Nfasc (4-fold), Gfra3 (3-fold), Unc5d (3-fold), and Crlf1 (3-fold).

The orl rat with inherited cryptorchidism has increased susceptibility to the testicular effects of in utero dibutyl phthalate exposure.

Phenotype results from interactions between genetics and environment, but for most environmental chemical exposures, such interactions are theoretical. The phenotypic response of the testis to in utero dibutyl phthalate (DBP) exposure was compared between two strains of Long-Evans (LE) rats, the orl substrain with inherited cryptorchidism and an outbred (wt) strain. orl and wt LE rats were exposed daily between gestational day (GD) 12 and GD21 to DBP dose levels ranging from 50 to 200 mg/kg by oral gavage and sensitive phthalate testicular end points examined at either GD19, GD21, or postnatal day (PND) 21.

Altered expression of muscle- and cytoskeleton-related genes in a rat strain with inherited cryptorchidism.

Development of the fetal gubernaculum is a prerequisite for testicular descent and dependent on insulin-like 3 and androgen, but knowledge of downstream effectors is limited. We analyzed transcript profiles in gubernaculum and testis to address changes occurring during normal and abnormal testicular descent in Long Evans wild-type (wt) and cryptorchid (orl) fetuses. Total RNA from male wt and orl gubernacula (gestational days [GD]18-20), wt female gubernacula (GD18), and testis (GD17 and 19) was hybridized to Affymetrix GeneChips.

Failure of shortening and inversion of the perinatal gubernaculum in the cryptorchid long-evans orl rat.

Purpose: Failure of testicular descent occurs in about 65% of spontaneously cryptorchid Long-Evans orl rats. Development of the fetal gubernaculum is dependent on expression of leucine rich G protein coupled receptor (also known as G protein coupled receptor affecting testicular descent) and its ligand, insulin-like 3. We studied testicular descent and mRNA expression of insulin-like 3 and leucine rich G protein coupled receptor in Long-Evans orl and Long-Evans wild-type rats during perinatal development.

Proteasome gene upregulation: a possible mechanism for intestinal adaptation.

Background/purpose: The mechanisms that control intestinal adaptation remain unknown. To better understand the adaptive process, microarray technology was used to analyze gene expression in a rat model of intestinal adaptation.

Methods: Adult male Sprague-Dawley rats underwent either a massive small bowel resection (70%) with anastomosis or a sham operation with small bowel transection and reanastomosis.