Fragile X syndrome is the leading monogenic cause of ASD. Trinucleotide repeats in the FMR1 gene abolish FMRP protein expression, leading to hyperactivation of ERK and mTOR signaling, upstream of mRNA translation. Here we show that metformin, the most widely used anti-type 2 diabetes drug, rescues core phenotypes in Fmr1-/y mice and selectively normalizes Erk signaling, Eif4e phosphorylation and the expression of Mmp9. Thus, metformin is a potential FXS therapeutic. Dysregulated mRNA translation is linked to core pathologies diagnosed in the Fragile X neurodevelopmental Syndrome (FXS), such as social and behavior problems, developmental delays and learning disabilities 1,2. In the brains of FXS patients and knockout mice (Fmr1-/y ; X-linked Fmr1 deletion in male mice), loss of Fragile X mental retardation protein (FMRP) results in hyperactivation of the mammalian/mechanistic target of rapamycin complex 1 (mTORC1) and the extracellular signal-regulated kinase (ERK) signaling pathways 1,2. Consistent with increased ERK activity, eukaryotic initiation factor 4E (eIF4E) phosphorylation is elevated in the brain of FXS patients and Fmr1-/y mice, thereby promoting translation of the mRNA encoding for matrix metalloproteinase 9 (MMP-9), which is elevated in the brains of both FXS patients and the Fmr1-/y mice 1-5. In accordance with these findings, knockout of Mmp9 rescues the majority of phenotypes in Fmr1-/y mice. MMP-9 degrades components of the extracellular matrix, including proteins important for synaptic function and maturation, which are implicated in FXS and autism spectrum disorders (ASD). Recent observations indicate that metformin, a first-line therapy for type 2 diabetes, imparts numerous health benefits beyond its original therapeutic use, such as decreased cancer risk and improved cancer prognosis 6. Metformin inhibits the mitochondrial respiratory chain complex 1, leading to a decrease in cellular energy state and thus activation of the energy sensor AMP-activated protein kinase (AMPK) 6. Several AMPK-independent activities of metformin have also been reported 7,8. Since metformin suppresses translation by inhibiting

Most patients hospitalized at tertiary care pediatric institutions receive at least 1 medication outside the terms of the Food and Drug Administration product license. Substantial variation in the frequency of off-label use was observed across diagnostic categories and drug classes. Despite the frequent off-label use of drugs, using an administrative database, we cannot determine which of these treatments are unsafe or ineffective and which treatments result in substantial benefit to the patient.

Background-Children with complex chronic conditions depend upon both their families and systems of pediatric health care, social services, and financing. Investigations into the workings of this ecology of care would be advanced by more accurate methods of population-level predictions of the likelihood for future hospitalization.

Nocturnal food intake was higher among NES participants, although their daily calorie intake was similar to that of controls. Reflecting their increased nocturnal intake, insulin (P < 0.001) and glucose levels (P = 0.07) among NES participants were higher than those of controls. Ghrelin levels were significantly lower in NES participants than in controls from 0100-0900 h (P = 0.003). Levels of plasma cortisol, melatonin, leptin, and prolactin did not differ between groups, but there was a trend for TSH levels (P = 0.07) to be higher during the 25 h in NES. NES participants had greater depressive symptoms than controls (P < 0.001). The differences in the levels of glucose, insulin, and ghrelin between NES and controls are closely associated with nocturnal food intake.

Increased health care utilization and charges reported in obese adults are also present in obese children. Most children with obesity had not been diagnosed as having obesity in this administrative data set.

Conditioned taste aversion (CTA) is an associative learning paradigm, wherein consumption of an appetitive tastant (e.g., saccharin) is paired to the administration of a malaise-inducing agent, such as intraperitoneal injection of LiCl. Aversive taste learning and retrieval require neuronal activity within the anterior insula (aIC) and the basolateral amygdala (BLA). Here, we labeled neurons of the aIC projecting to the BLA in adult male mice using a retro-AAV construct and assessed their necessity in aversive and appetitive taste learning. By restricting the expression of chemogenetic receptors in aIC-to-BLA neurons, we demonstrate that activity within the aICto-BLA projection is necessary for both aversive taste memory acquisition and retrieval, but not for its maintenance, nor its extinction. Moreover, inhibition of the projection did not affect incidental taste learning per se, but effectively suppressed aversive taste memory retrieval when applied either during or before the encoding of the unconditioned stimulus for CTA (i.e., malaise). Remarkably, activation of the projection after novel taste consumption, without experiencing any internal discomfort, was sufficient to form an artificial aversive taste memory, resulting in strong aversive behavior upon retrieval. Our results indicate that aIC-to-BLA projecting neurons are an essential component in the ability of the brain to associate taste sensory stimuli with body states of negative valence and guide the expression of valence-specific behavior upon taste memory retrieval.

To evaluate the short-and long-term adverse effects of systemic glucocorticosteroid (GS) therapy in infants with hemangiomas.Design: Retrospective chart review of infants treated with GSs for hemangiomas during a 3-year period.Setting: Tertiary care children's hospital Patients: Of 141 patients identified with hemangiomas, 22 were treated with GSs.Interventions: Minimum of 1-month GS therapy at a minimum starting dose of 0.5 mg/kg per day.Outcome Measures: Demographic and anthropometric measurements, starting dose and duration of GS therapy, subjective parental concerns, complications related to hemangioma, adjunctive treatment, and morning cortisol levels and/or results of corticotropin stimulation tests. Results:The average starting dose was 2.23 mg/kg per day; average length of therapy was 28.1 weeks. Complaints of irritability, fussiness, or insomnia were identified in 16 patients (73%). Hypertension, defined as 3 or more episodes of systolic blood pressure higher than 105 mm Hg, was observed in 10 patients (45%). Morning cortisol levels were abnormal in 13 (87%) of the 15 patients evaluated. Low-dose corticotropin stimulation test results were abnormal in 2 of the 3 infants tested.Conclusions: While GS therapy for infantile hemangiomas was tolerated well overall, changes in behavior, insomnia, and gastrointestinal symptoms were common parental concerns. Hypertension and hypothalamicpituitary-adrenal axis suppression were observed frequently. Infants undergoing long-term GS treatment of hemangiomas should be monitored carefully for these potential adverse effects.

Physicians treating children with asthma, bronchiolitis, and croup in US emergency departments are underusing known effective treatments and overusing ineffective or unproven therapies and diagnostic tests.