Attention-deficit hyperactivity disorder is associated with disordered eating in adolescents.

AIM: Attention-deficit hyperactivity disorder (ADHD) and disordered eating (DE) are both highly prevalent among adolescents, but their relationship is understudied. This study examines their possible association in a nationally representative sample of adolescents. METHODS: Participants in the Israeli Youth Health and Nutrition Survey (2015-2016), a cross-sectional, school-based study, completed self-administered questionnaires, including the SCOFF questionnaire, and underwent anthropometric measurements. An affirmative reply to at least two SCOFF items was considered a DE case. Multivariable logistic regression evaluated the ADHD-DE association and the associations between ADHD and individual SCOFF items, controlling for age, sex, socioeconomic status, and body mass index. RESULTS: Of 4616 participants (12-18 years, 50.2% male), 654 reported an ADHD diagnosis. DE prevalence among ADHD adolescents was significantly higher than the non-ADHD group (50.2% vs. 43.9%, p = 0.003). Controlling for potential covariates, the association between ADHD and DE remained significant (OR = 1.409; 95% CI: 1.170-1.697), as did associations between ADHD and three SCOFF items. No difference in DE prevalence was found between stimulant-treated (n = 287) and untreated (n = 326) adolescents with ADHD. CONCLUSION: Adolescents with ADHD are more likely to experience DE. As DE can herald an imminent eating disorder, early identification is crucial. Further studies are needed to determine the ADHD-DE relationship's causality. IMPACT: Disordered eating (DE) and attention-deficit hyperactivity disorder (ADHD) are common among adolescents, and significantly affect health and well-being. This study examined the association between ADHD and DE in adolescents using the SCOFF questionnaire. Following adjustment for sociodemographic variables and BMI z-score, ADHD was associated with a 41% increased odds for DE. This study established the association between ADHD and DE, using a well-known questionnaire, in a large, nationally representative sample of adolescents. Monitoring eating behaviors and attitudes among adolescents with ADHD should be a priority, to minimize the risk of developing an eating disorder and its harmful consequences.

Attention-deficit hyperactivity disorder is associated with relatively short stature among adolescents.

AIM: To estimate the association between attention-deficit hyperactivity disorder (ADHD) and relatively short stature (RSS) among adolescents. METHODS: Participants in the Israeli Youth Health and Nutrition Survey (2015-2016), a cross-sectional school-based study, completed self-administered questionnaires and underwent anthropometric measurements. Height z-score < -0.7 (<25th percentile) was defined as RSS. Multivariable logistic regression analyses assessed the relation between ADHD and RSS, controlling for age, sex, body mass index (BMI) and socioeconomic status (Basic Model), and also for lifestyle factors such as physical activity, sleep duration, dietary patterns and intakes. RESULTS: Of 4173 participants (11-18 years, 50.2% males), 654 self-reported ever being diagnosed with ADHD; 3519 participants were controls. Overweight (BMI z-score ≥1) and pubertal status were not different among groups. According to the Basic Model, ADHD was significantly associated with RSS (OR 1.25, 95% CI 1.03-1.50), and even after adjustments for lifestyle factors and dietary intake (OR 1.28, 95% CI 1.03-1.58). Stimulant-treated ADHD adolescents had similar height z-scores and lifestyles as those not treated with stimulants. CONCLUSION: Attention-deficit hyperactivity disorder was associated with RSS. Height deficit may be intrinsic to ADHD or its pharmacotherapy, rather than a consequence of lifestyle alone. Further studies are needed to determine the causal relationship between ADHD and short stature.

Non-Dairy Animal Protein Consumption Is Positively Associated with Overweight and Obesity in Israeli Adolescents.

Protein consumption apparently plays a role in weight control. This cross-sectional study examined the association of protein consumption in Israeli adolescents with overweight/obesity. 7th−12th grade students participating in a national school-based survey (2015−2016) completed self-administered questionnaires, including a food frequency questionnaire, and height and weight measurements (n = 3443, 48% males, 15.2 ± 1.6 years). WHO growth standards served to define weight status. Intakes of total protein and protein source were calculated. Multivariable logistic regression analyses evaluated associations with overweight/obesity (BMI z-score ≥ 1), adjusting for possible covariates. Total protein intake (median (IQR)) was 62.5 (45.5, 85.7) g/d, accounting for 12.0 (10.5, 13.6) percent of daily energy. Of participants, 31.4% were overweight/obese. In multivariable models, overweight/obesity was positively associated with incremental increases of 10 g/d in total protein intake (OR = 1.07, 95% CI: 1.02−1.12, p < 0.01), total animal protein intake (OR = 1.05, 95% CI: 1.01−1.10, p = 0.026), and non-dairy animal protein intake (OR = 1.06, 95% CI: 1.01−1.11, p = 0.029). No associations were found with plant or dairy protein intake. These associations remained when protein intake was reported as a percentage of daily energy and when overweight and obesity were analyzed individually. High daily protein intakes, principally from non-dairy animal sources, were positively associated with overweight/obesity in adolescents. Additional studies are needed to establish causality of these findings.

Milk and dairy consumption is positively associated with height in adolescents: results from the Israeli National Youth Health and Nutrition Survey.

PURPOSE: Milk consumption is associated with increased height primarily in early childhood. However, in adolescents, data are scarce with inconsistent results. Since height is a proxy for overall health and well-being, this study evaluated the association of dairy intake with height in adolescents. METHODS: Students in 7th-12th grades, participating in the 2015-2016 Israeli Health and Nutrition Youth Survey, a school-based cross-sectional study, completed self-administered questionnaires, including a semi-quantitative food frequency questionnaire (n = 3529, 48% males, 15.2 ± 1.6 years). Anthropometric measurements were also performed. Dairy servings were calculated as the calcium equivalent of 1 cup of milk, and consumption was divided into four categories from very low (< 1 serving/day) to high (3 + servings/day). BMI- and Height-for-age z scores (HAZs) were calculated according to WHO growth standard; relatively short stature (RSS) was defined as HAZ < - 0.7 SD (< 25th percentile). Multivariable linear and logistic regression analyses were performed to evaluate the association of dairy intake with HAZ and prevalence of RSS, respectively. RESULTS: Median consumption of dairy products was 2 servings/day, 1.4 from unsweetened products (milk, cheese and yogurt). Controlling for age, sex, BMI-z-score and socioeconomic status, each increment of unsweetened dairy intake was associated with on average 0.04 higher HAZ (equivalent to 0.3-0.4 cm, p < 0.05), and with reduced risk for RSS: OR 0.90, 95%CI: 0.84, 0.97, p < 0.01. No such associations were found with sweetened dairy products. CONCLUSION: Consumption of unsweetened dairy products (3-4 servings/day) appears to contribute to achieving growth potential in adolescents. Intervention studies are necessary to determine the causal relationship between dairy intake and linear growth.

T and B Cell Receptor Immune Repertoire Analysis using Next-generation Sequencing.

Immunological memory, the hallmark of adaptive immunity, is orchestrated by T and B lymphocytes. In circulation and different organs, there are billions of unique T and B cell clones, and each one can bind a specific antigen, leading to proliferation, differentiation and/or cytokine secretion. The vast heterogeneity in T and B cells is generated by random recombination of different genetic segments. Next-generation sequencing (NGS) technologies, developed in the last decade, enable an unprecedented in-depth view of the T and B cell receptor immune repertoire. Studies in various inflammatory conditions, immunodeficiencies, infections and malignancies demonstrated marked changes in clonality, gene usage, and biophysical properties of immune repertoire, providing important insights about the role of adaptive immune responses in different disorders. Here, we provide a detailed protocol for NGS of immune repertoire of T and B cells from blood and tissue. We present a pipeline starting from DNA isolation through library preparation, sequencing on NGS sequencer and ending with basic analyses. This method enables exploration of specific T and B cells at the nucleotide or amino-acid level, and thus can identify dynamic changes in lymphocyte populations and diversity parameters in different diseases. This technique is slowly entering clinical practice and has the potential for identification of novel biomarkers, risk stratification and precision medicine.

A phase II study of bisantrene in patients with relapsed/refractory acute myeloid leukemia.

OBJECTIVES: To determine the current role of bisantrene, an anthracene with anthracycline-like activity which was shown in earlier studies to be effective therapy in relapsed/refractory acute myeloid leukemia with no discernible cardiotoxicity, in the treatment of patients with R/R AML. METHODS: This phase 2, single-center study (NCT03820908) enrolled adult R/R AML to receive bisantrene (250 mg/m2 daily for 7 days) which was administered via an intravenous infusion over 2 hours on days 1-7. Disease assessment included routine blood work and bone marrow studies. RESULTS: In all, 10 patients were enrolled with a median of 3 lines of prior therapy including seven patients who had relapsed following allogeneic stem cell transplantation. The most frequently reported grade ≥3 treatment-attributed hematologic AE was thrombocytopenia, whereas the most frequently reported grade ≥3 treatment-attributed non-hematologic AE was mucositis. Of the 10 patients, one (10%) achieved a complete remission and three patients achieved a partial remission resulting in an overall response rate of 40%. Next-generation sequencing of patient samples identified a wide array of mutations associated with activated signaling, splicing, and epigenetic modification. CONCLUSIONS: In view of the observed low toxicity, a follow-up study combining bisantrene with complementary anti-leukemic therapy is planned.

Whole-genome sequencing reveals principles of brain retrotransposition in neurodevelopmental disorders.

Neural progenitor cells undergo somatic retrotransposition events, mainly involving L1 elements, which can be potentially deleterious. Here, we analyze the whole genomes of 20 brain samples and 80 non-brain samples, and characterized the retrotransposition landscape of patients affected by a variety of neurodevelopmental disorders including Rett syndrome, tuberous sclerosis, ataxia-telangiectasia and autism. We report that the number of retrotranspositions in brain tissues is higher than that observed in non-brain samples and even higher in pathologic vs normal brains. The majority of somatic brain retrotransposons integrate into pre-existing repetitive elements, preferentially A/T rich L1 sequences, resulting in nested insertions. Our findings document the fingerprints of encoded endonuclease independent mechanisms in the majority of L1 brain insertion events. The insertions are "non-classical" in that they are truncated at both ends, integrate in the same orientation as the host element, and their target sequences are enriched with a CCATT motif in contrast to the classical endonuclease motif of most other retrotranspositions. We show that L1Hs elements integrate preferentially into genes associated with neural functions and diseases. We propose that pre-existing retrotransposons act as "lightning rods" for novel insertions, which may give fine modulation of gene expression while safeguarding from deleterious events. Overwhelmingly uncontrolled retrotransposition may breach this safeguard mechanism and increase the risk of harmful mutagenesis in neurodevelopmental disorders.

ADAR1 deletion induces NFκB and interferon signaling dependent liver inflammation and fibrosis.

Adenosine deaminase acting on RNA (ADAR) 1 binds and edits double-stranded (ds) RNA secondary structures found mainly within untranslated regions of many transcripts. In the current research, our aim was to study the role of ADAR1 in liver homeostasis. As previous studies show a conserved immunoregulatory function for ADAR1 in mammalians, we focused on its role in preventing chronic hepatic inflammation and the associated activation of hepatic stellate cells to produce extracellular matrix and promote fibrosis. We show that hepatocytes specific ADAR1 knock out (KO) mice display massive liver damage with multifocal inflammation and fibrogenesis. The bioinformatics analysis of the microarray gene-expression datasets of ADAR1 KO livers reveled a type-I interferons signature and an enrichment for immune response genes compared to control littermate livers. Furthermore, we found that in vitro silencing of ADAR1 expression in HepG2 cells leads to enhanced transcription of NFκB target genes, foremost of the pro-inflammatory cytokines IL6 and IL8. We also discovered immune cell-independent paracrine signaling among ADAR1-depleted HepG2 cells and hepatic stellate cells, leading to the activation of the latter cell type to adopt a profibrogenic phenotype. This paracrine communication dependent mainly on the production and secretion of the cytokine IL6 induced by ADAR1 silencing in hepatocytes. Thus, our findings shed a new light on the vital regulatory role of ADAR1 in hepatic immune homeostasis, chiefly its inhibitory function on the crosstalk between the NFκB and type-I interferons signaling cascades, restraining the development of liver inflammation and fibrosis.

Activation-Induced Cytidine Deaminase Links Ovulation-Induced Inflammation and Serous Carcinogenesis.

In recent years, the notion that ovarian carcinoma results from ovulation-induced inflammation of the fallopian tube epithelial cells (FTECs) has gained evidence. However, the mechanistic pathway for this process has not been revealed yet. In the current study, we propose the mutator protein activation-induced cytidine deaminase (AID) as a link between ovulation-induced inflammation in FTECs and genotoxic damage leading to ovarian carcinogenesis. We show that AID, previously shown to be functional only in B lymphocytes, is expressed in FTECs under physiological conditions, and is induced in vitro upon ovulatory-like stimulation and in vivo in carcinoma-associated FTECs. We also report that AID activity results in epigenetic, genetic and genomic damage in FTECs. Overall, our data provides new insights into the etiology of ovarian carcinogenesis and may set the ground for innovative approaches aimed at prevention and early detection.

Identification of genomic aberrations in hemangioblastoma by droplet digital PCR and SNP microarray highlights novel candidate genes and pathways for pathogenesis.

BACKGROUND: The genetic mechanisms underlying hemangioblastoma development are still largely unknown. We used high-resolution single nucleotide polymorphism microarrays and droplet digital PCR analysis to detect copy number variations (CNVs) in total of 45 hemangioblastoma tumors. RESULTS: We identified 94 CNVs with a median of 18 CNVs per sample. The most frequently gained regions were on chromosomes 1 (p36.32) and 7 (p11.2). These regions contain the EGFR and PRDM16 genes. Recurrent losses were located at chromosome 12 (q24.13), which includes the gene PTPN11. CONCLUSIONS: Our findings provide the first high-resolution genome-wide view of chromosomal changes in hemangioblastoma and identify 23 candidate genes: EGFR, PRDM16, PTPN11, HOXD11, HOXD13, FLT3, PTCH, FGFR1, FOXP1, GPC3, HOXC13, HOXC11, MKL1, CHEK2, IRF4, GPHN, IKZF1, RB1, HOXA9, and micro RNA, such as hsa-mir-196a-2 for hemangioblastoma pathogenesis. Furthermore, our data implicate that cell proliferation and angiogenesis promoting pathways may be involved in the molecular pathogenesis of hemangioblastoma.

A novel postpriming regulatory check point of effector/memory T cells dictated through antigen density threshold-dependent anergy.

CTLs act as the effector arm of the cell-mediated immune system to kill undesirable cells. Two processes regulate these effector cells to prevent self reactivity: a thymic selection process that eliminates autoreactive clones and a multistage activation or priming process that endows them with a license to kill cognate target cells. Hitherto no subsequent regulatory restrictions have been ascribed for properly primed and activated CTLs that are licensed to kill. In this study we show that CTLs possess a novel postpriming regulatory mechanism(s) that influences the outcome of their encounter with cognate target cells. This mechanism gauges the degree of Ag density, whereupon reaching a certain threshold significant changes occur that induce anergy in the effector T cells. The biological consequences of this Ag-induced postpriming control includes alterations in the expression of cell surface molecules that control immunological synapse activity and cytokine profiles and induce retarded cell proliferation. Most profound is genome-wide microarray analysis that demonstrates changes in the expression of genes related to membrane potential, TCR signal transduction, energy metabolism, and cell cycle control. Thus, a discernible and unique gene expression signature for anergy as a response to high Ag density has been observed. Consequently, activated T cells possess properties of a self-referential sensory organ. These studies identify a new postpriming control mechanism of CTL with anergenic-like properties. This mechanism extends our understanding of the control of immune function and regulation such as peripheral tolerance, viral infections, antitumor immune responses, hypersensitivity, and autoimmunity.

Large-scale identification of leaf senescence-associated genes.

Leaf senescence is a form of programmed cell death, and is believed to involve preferential expression of a specific set of "senescence-associated genes" (SAGs). To decipher the molecular mechanisms and the predicted complex network of regulatory pathways involved in the senescence program, we have carried out a large-scale gene identification study in a reference plant, Arabidopsis thaliana. Using suppression subtractive hybridization, we isolated approximately 800 cDNA clones representing SAGs expressed in senescing leaves. Differential expression was confirmed by Northern blot analysis for 130 non-redundant genes. Over 70 of the identified genes have not previously been shown to participate in the senescence process. SAG-encoded proteins are likely to participate in macromolecule degradation, detoxification of oxidative metabolites, induction of defense mechanisms, and signaling and regulatory events. Temporal expression profiles of selected genes displayed several distinct patterns, from expression at a very early stage, to the terminal phase of the senescence syndrome. Expression of some of the novel SAGs, in response to age, leaf detachment, darkness, and ethylene and cytokinin treatment was compared. The large repertoire of SAGs identified here provides global insights about regulatory, biochemical and cellular events occurring during leaf senescence.