Kras(G12D) and Nkx2-1 haploinsufficiency induce mucinous adenocarcinoma of the lung.

Mucinous adenocarcinoma of the lung is a subtype of highly invasive pulmonary tumors and is associated with decreased or absent expression of the transcription factor NK2 homeobox 1 (NKX2-1; also known as TTF-1). Here, we show that haploinsufficiency of Nkx2-1 in combination with oncogenic Kras(G12D), but not with oncogenic EGFR(L858R), caused pulmonary tumors in transgenic mice that were phenotypically similar to human mucinous adenocarcinomas. Gene expression patterns distinguished tumor goblet (mucous) cells from nontumorigenic airway and intestinal goblet cells.

Association of parent ratings of executive function with global- and setting-specific behavioral impairment after adolescent traumatic brain injury.

Objective: To determine the association of primary caregiver-rated behavioral and metacognitive aspects of executive function (EF) with impaired functioning after adolescent traumatic brain injury (TBI).

Design: Multicenter cross-sectional study.

Setting: Outpatient.

Physical activity monitoring in adolescents with juvenile fibromyalgia: findings from a clinical trial of cognitive-behavioral therapy.

Objective: Juvenile fibromyalgia (JFM) is a chronic musculoskeletal pain condition that is associated with reduced physical function. Recent research has demonstrated that cognitive-behavioral therapy (CBT) is effective in improving daily functioning among adolescents with JFM. However, it is not known whether these improvements were accompanied by increased physical activity levels.

Adolescents' internalizing problems following traumatic brain injury are related to parents' psychiatric symptoms.

Background: A small body of previous research has demonstrated that pediatric traumatic brain injury (TBI) increases risk for internalizing problems, but findings have varied regarding their predictors and correlates.

Methods: We examined the level and correlates of internalizing symptoms in 130 teens who had sustained a complicated mild to severe TBI within the past 1 to 6 months. Internalizing problems were measured via both maternal- and paternal-report Child Behavior Checklist.

Corticosteroids for the treatment of infantile spasms: a systematic review.

Adrenocorticotropic hormone (ACTH) and corticosteroids are the usual first-line treatment options for infantile spasms. Despite significant differences, these agents are often lumped together in this context. There is a need to systematically explore the efficacy of corticosteroids in the treatment of infantile spasms, especially in comparison to ACTH.

Predictors of treatment response in depressed mothers receiving in-home cognitive-behavioral therapy and concurrent home visiting.

Home visiting is a child abuse prevention strategy that seeks to optimize child development by providing mothers with support, training, and parenting information. Research has consistently found high rates of depression in mothers participating in home visiting programs and low levels of obtaining mental health treatment in the community. Successful treatment of depressed mothers in home visiting programs holds the potential to improve maternal and child outcomes.

Association of noninvasively measured renal protein biomarkers with histologic features of lupus nephritis.

Objective: To investigate the relationship of urinary biomarkers and established measures of renal function to histologic findings in lupus nephritis (LN), and to test whether certain combinations of the above-mentioned laboratory measures are diagnostic for specific histologic features of LN.

Methods: Urine samples from 76 patients were collected within 2 months of kidney biopsy and assayed for the urinary biomarkers lipocalin-like prostaglandin D synthase (L-PGDS), α(1) -acid glycoprotein (AAG), transferrin (TF), ceruloplasmin (CP), neutrophil gelatinase-associated lipocalin (NGAL), and monocyte chemotactic protein 1 (MCP-1). Using nonparametric analyses, levels of urinary biomarkers and established markers of renal function were compared with histologic features seen in LN, i.

Importance of muscle light microscopic mitochondrial subsarcolemmal aggregates in the diagnosis of respiratory chain deficiency.

The purpose of this study was to evaluate relationships between subsarcolemmal mitochondrial aggregates and electron transport chain deficiencies in skeletal muscle with the objective of establishing an association between mitochondrial accumulation and electron transport chain complex deficiency. We conducted a large-scale, retrospective study to evaluate factors associated with subsarcolemmal mitochondrial aggregates (percent) in pediatric patients who received muscle biopsies for suspected respiratory chain disorders. Patients were included if they had histochemical stains for assessment of mitochondrial pathology and had biochemical testing for muscle electron transport chain complex activities.

Hemophagocytic lymphohistiocytosis: updates and evolving concepts.

Purpose Of Review: Hemophagocytic lymphohistiocytosis (HLH) is an immune dysregulatory syndrome that is associated with underlying defects of perforin-dependent cytotoxic function. This review seeks to update readers on new scientific insights and evolving clinical concepts related to this rare but fatal disorder.

Recent Findings: Clinically, HLH is defined by severe inflammation and potentially fatal damage to a variety of organ systems including the bone marrow, liver, or brain.

Ubiquinone (coenzyme Q10) prevents renal mitochondrial dysfunction in an experimental model of type 2 diabetes.

Cardiovascular benefits of ubiquinone have been previously demonstrated, and we administered it as a novel therapy in an experimental model of type 2 diabetic nephropathy. db/db and dbH mice were followed for 10 weeks, after randomization to receive either vehicle or ubiquinone (CoQ10; 10mg/kg/day) orally. db/db mice had elevated urinary albumin excretion rates and albumin:creatinine ratio, not seen in db/db CoQ10-treated mice.

Cognitive behavioral therapy for the treatment of juvenile fibromyalgia: a multisite, single-blind, randomized, controlled clinical trial.

Objective: Juvenile fibromyalgia syndrome (FMS) is a chronic musculoskeletal pain disorder in children and adolescents for which there are no evidence-based treatments. The objective of this multisite, single-blind, randomized clinical trial was to test whether cognitive-behavioral therapy (CBT) was superior to fibromyalgia (FM) education in reducing functional disability, pain, and symptoms of depression in juvenile FMS.

Methods: Participants were 114 adolescents (ages 11-18 years) with juvenile FMS.

Identification of a novel ZIC3 isoform and mutation screening in patients with heterotaxy and congenital heart disease.

Patients with heterotaxy have characteristic cardiovascular malformations, abnormal arrangement of their visceral organs, and midline patterning defects that result from abnormal left-right patterning during embryogenesis. Loss of function of the transcription factor ZIC3 causes X-linked heterotaxy and isolated congenital heart malformations and represents one of the few known monogenic causes of congenital heart disease. The birth incidence of heterotaxy-spectrum malformations is significantly higher in males, but our previous work indicated that mutations within ZIC3 did not account for the male over-representation.

Gene Expression Profiles from Peripheral Blood Mononuclear Cells Are Sensitive to Short Processing Delays.

In the analysis of peripheral blood gene expression, timely processing of samples is essential to ensure that measurements reflect in vivo biology, rather than ex vivo sample processing variables. The effect of processing delays on global gene expression patterns in peripheral blood mononuclear cells (PBMCs) was assessed by isolating and stabilizing PBMC-derived RNA from 3 individuals either immediately after phlebotomy or after a 4 h delay. RNA was labeled using NuGEN Ovation labeling and probed using the Affymetrix HG U133 Plus 2.

Genetic diagnosis in pediatric cardiomyopathy: clinical application and research perspectives.

There has been tremendous growth in the application of genetics to the clinical practice of pediatric cardiomyopathy. The identification of the genetic basis for cardiomyopathies is important for establishing a causal diagnosis, providing definitive identification of at risk family members, and providing cost-effective screening and surveillance. Additional research is needed to better understand the genetic heterogeneity of cardiomyopathy in children, the implications of specific genotypes, the best approach to cardiac surveillance and genetic testing, and the utility of genotyping for individual risk stratification.

Influence of treatment for disruptive behavior disorders on adrenal and gonadal hormones in youth.

The study examined whether psychosocial intervention for children diagnosed with a disruptive behavior disorder (DBD; n = 84) changed concentrations of cortisol and testosterone across a 3-year follow-up when compared to a matched, nonclinical, healthy comparison (HC; n = 69) group. Boys and girls (6-11 years) with a DBD were randomly assigned to one of two arms of a multimethod intervention. Hierarchical linear modeling revealed that children undergoing psychosocial intervention for a DBD experienced a significant decline in diurnal cortisol change over time (p < .

Ghrelin biology and its role in weight-related disorders.

The discovery of ghrelin and its role in human metabolism has promoted significant research and advances in the study of obesity and other weight-related disorders. Ghrelin is relevant to many disorders of metabolism and weight such as obesity, cachexia, Prader-Willi Syndrome (PWS), and Anorexia Nervosa (AN), and its role in the pathophysiology differs. The changes observed in ghrelin physiology in these disorders shed light on the overall role of ghrelin in human metabolism and growth.

Integrin α6β4 defines a novel lung epithelial progenitor cell: a step forward for cell-based therapies for pulmonary disease.

The many challenges associated with lung transplantation provide a strong rationale for the development of cell- and tissue-based therapies for patients with respiratory failure caused by the loss of lung tissue that is associated with chronic pulmonary disease, injury, or resection. In this issue of the JCI, Chapman et al. take an important step forward in the development of regenerative medicine for the treatment of lung disease by identifying a novel integrin α6β4-expressing alveolar epithelial cell that serves as a multipotent progenitor during repair of the severely injured lung.

Perforin is a critical physiologic regulator of T-cell activation.

Individuals with impaired perforin-dependent cytotoxic function (Ctx(-)) develop a fatal inflammatory disorder called hemophagocytic lymphohistiocytosis (HLH). It has been hypothesized that immune hyperactivation during HLH is caused by heightened infection, defective apoptosis/responsiveness of Ctx(-) lymphocytes, or enhanced antigen presentation. Whereas clinical and experimental data suggest that increased T-cell activation drives HLH, potential abnormalities of T-cell activation have not been well characterized in Ctx(-) hosts.

Clinical utility and validity of the Functional Disability Inventory among a multicenter sample of youth with chronic pain.

The Functional Disability Inventory (FDI) is a well-established and commonly used measure of physical functioning and disability in youth with chronic pain. Further validation of the measure has been called for, in particular, examination of the clinical utility and factor structure of the measure. To address this need, we utilized a large multicenter dataset of pediatric patients with chronic pain who had completed the FDI and other measures assessing pain and emotional functioning.

Use of transgenic mouse models to understand the origins of familial pulmonary fibrosis.

Pulmonary fibrosis is an unremitting degenerative lung disease that has an associated high mortality. The major pathological features include the growth of fibroblasts, emergence of myofibroblasts and their production of extracellular matrix that distorts the peripheral lung tissue and impairs respiratory function. Efforts to pharmacologically reduce inflammation, inhibit fibroblast growth, or matrix synthesis have not been successful in ameliorating disease.

Use of the Autism Diagnostic Observation Schedule (ADOS) in a clinical setting.

The aim of this study was to examine the Autism Diagnostic Observation Schedule (ADOS) as it is commonly used in clinical practice. ADOS classifications were compared to final diagnoses given by a multidisciplinary team to 584 children referred for evaluation for possible autism spectrum disorder (ASD) at the Cincinnati Children's Hospital Medical Center. A total of 177 children were evaluated with a Module 1 (87 No Words), 198 with a Module 2 (90 < 5 years) and 209 with a Module 3.

Innate dysfunction promotes linear growth failure in pediatric Crohn's disease and growth hormone resistance in murine ileitis.

Background: Growth failure remains a common complication of pediatric Crohn's disease (CD) and has been associated with small bowel involvement and need for surgery. We have reported that patients with elevated (≥ 1.6 μg/mL) granulocyte macrophage colony stimulating factor autoantibodies (GM-CSF Ab) are more likely to experience complicated ileal disease requiring surgery.

Endothelial cell-specific deletion of transcription factor FoxM1 increases urethane-induced lung carcinogenesis.

Vascular endothelial cells provide essential support to the tumor microenvironment, but little is known about the transcriptional control of endothelial functions during tumorigenesis. Here we define a critical role for the Forkhead transcription factor FoxM1 in modulating the development of tumor-associated endothelial cells. Pulmonary tumorigenesis induced by urethane administration was compared in mice genetically deleted for FoxM1 in endothelial cells (enFoxm1(-/-) mice).

RhoH regulates subcellular localization of ZAP-70 and Lck in T cell receptor signaling.

RhoH is an hematopoietic-specific, GTPase-deficient Rho GTPase that plays a role in T development. We investigated the mechanisms of RhoH function in TCR signaling. We found that the association between Lck and CD3ζ was impaired in RhoH-deficient T cells, due to defective translocation of both Lck and ZAP-70 to the immunological synapse.

Acquired coenzyme Q10 deficiency in children with recurrent food intolerance and allergies.

The current study evaluated 23 children (ages 2-16 years) with recurrent food intolerance and allergies for CoQ10 deficiency and mitochondrial abnormalities. Muscle biopsies were tested for CoQ10 levels, pathology, and mitochondrial respiratory chain (MRC) activities. Group 2 (age >10 years; n = 9) subjects had significantly decreased muscle CoQ10 than Group 1 (age <10 y; n = 14) subjects (p = 0.