Epidemiological studies have shown that adolescent smoking is associated with health risk behaviors, including high-risk sexual activity and illicit drug use. Using rat as an animal model, we evaluated the behavioral and biochemical effects of a 4-day, low-dose nicotine pretreatment (60 mg/kg; intravenous) during adolescence and adulthood. Nicotine pretreatment significantly increased initial acquisition of cocaine self-administration, quinpirole-induced locomotor activity, and penile erection in adolescent rats, aged postnatal day (P)32. These effects were long lasting, remaining evident 10 days after the last nicotine treatment, and were observed when nicotine pretreatment was administered during early adolescence (P28-31), but not late adolescence (P38-41) or adulthood (P86-89). Neurochemical analyses of c-fos mRNA expression, and of monoamine transmitter and transporter levels, showed that forebrain limbic systems are continuing to develop during early adolescence, and that this maturation is critically altered by brief nicotine exposure. Nicotine selectively increased c-fos mRNA expression in the nucleus accumbens shell and basolateral amygdala in adolescent, but not adult animals, and altered serotonin markers in these regions as well as the prefrontal cortex. Nicotine enhancement of cocaine self-administration and quinpirole-induced locomotor activity was blocked by co-administration of WAY 100 635 (N-{2-[4-(2-methoxyphenyl)-1-piperazinyl] ethyl}-N-(2-pyridinyl)cyclohexanecarboxamide), a selective serotonin 1A (5-HT1A) receptor antagonist. Early adolescent pretreatment with the mixed autoreceptor/heteroceptor 5-HT1A receptor agonist, 8-OH-DPAT, but not the autoreceptor-selective agonist, S-15535, also enhanced quinpirole-induced locomotor activation. Nicotine enhancement of quinpirole-induced penile erection was not blocked by WAY 100 635 nor mimicked by 8-OH-DPAT. These findings indicate that early adolescent nicotine exposure uniquely alters limbic function by both 5-HT1A and non-5-HT1A receptor mechanisms.

Since adolescence is a critical period for the initiation of tobacco use, we have systematically compared behavioral and endocrine responses to nicotine in Sprague-Dawley rats of both sexes at early adolescence (postnatal day (P) 28), mid- adolescence (P38) and adulthood (P90). Locomotion and center time in a novel open field were evaluated for 30 min following intravenous injection of saline or nicotine (60 µg/kg), followed by measurement of plasma corticosterone. Complex age and sex differences in behavioral and endocrine response were observed, which were dependent on the functional endpoint examined. Whereas there were age differences in nicotine effects on all functional measures, sex differences were largely restricted to adult stress-related corticosterone and center-time responses. Although significant drug effects were detected at P28 and P90, there was no effect of nicotine at P38 on any measure examined. In saline-treated males, but not females, there were significant positive correlations across age between initial ambulatory counts and both initial vertical counts and total center time. Nicotine treatment increased correlations in both sexes, and yielded a significant negative interaction between initial ambulatory counts and plasma corticosterone. The unique responses of adolescents to nicotine are consistent with an immature function of nicotinic acetylcholine receptors at this age.

Common thought is that increased frequency and severity of headache may reflect secondary pathology; however, headache phenotype may not be fully developed and can evolve in adolescence or adulthood. Headache location, particularly occipital headache alone, does not necessarily signify secondary intracranial pathology. Certain warning signs warrant neuroimaging, but others only warrant imaging in certain clinical contexts. Brain MRI is the neuroimaging modality of choice, though there is a high rate of incidental findings and often does not change headache management. A stepwise approach is essential to avoid missing secondary headaches. There are several differences between adults and children in clinical manifestations of headache. Evaluation and diagnosis of pediatric headache starts with a thorough headache and medical history, family and social history, and identification of risk factors. A thorough physical and neurologic exam is important, with close attention to features that could suggest secondary headache pathology. Neuroimaging and other testing should only be performed if there is concern for secondary headache.

Rationale Epidemiological evidence of early adolescent tobacco use, prior to that of marijuana and other illicit drugs, has led to the hypothesis that nicotine is a "gateway" drug that sensitizes reward pathways to the addictive effects of other psychostimulants. Objective To test this hypothesis, we have compared the effect of a brief, low-dose nicotine pretreatment of adolescent and adult rats on subsequent locomotor response to acute and chronic cocaine. Materials and methods Adolescents, aged postnatal day (P) 28, and adults, aged P86, were given four daily injections of saline or nicotine (0.06 mg/kg, i.v.). At P32 and P90, rats were given acute injections of cocaine (0, 0.4 or 1.0 mg/kg, i.v.) and monitored for locomotor activity in either a habituated or novel test environment. To examine cocaine sensitization, rats were treated for 3 days with saline or cocaine (0.4 mg/kg, i.v.), and, after 1 day of withdrawal, were given a challenge dose of cocaine (0.4 mg/kg, i.v.). Results Nicotine pretreatment did not affect acute, druginduced locomotor activity at either age. However, age differences in cocaine response were observed, with adolescent animals showing enhanced locomotor activity in the novel environment. Adolescent controls did not exhibit cocaine-induced locomotor sensitization, whereas adults did. Nicotine pretreatment during adolescence promoted the development and expression of a sensitized response to repeated cocaine exposure similar to that observed in saline-pretreated adult controls. Conclusions These findings show that brief pretreatment with nicotine, in a low dose comparable to that inhaled in 2-4 cigarettes, enhances cocaine-induced behavioral plasticity in adolescent rats.

ImportanceIt is currently unknown how often and in which ways a genetic diagnosis given to a patient with epilepsy is associated with clinical management and outcomes.ObjectiveTo evaluate how genetic diagnoses in patients with epilepsy are associated with clinical management and outcomes.Design, Setting, and ParticipantsThis was a retrospective cross-sectional study of patients referred for multigene panel testing between March 18, 2016, and August 3, 2020, with outcomes reported between May and November 2020. The study setting included a commercial genetic testing laboratory and multicenter clinical practices. Patients with epilepsy, regardless of sociodemographic features, who received a pathogenic/likely pathogenic (P/LP) variant were included in the study. Case report forms were completed by all health care professionals.ExposuresGenetic test results.Main Outcomes and MeasuresClinical management changes after a genetic diagnosis (ie, 1 P/LP variant in autosomal dominant and X-linked diseases; 2 P/LP variants in autosomal recessive diseases) and subsequent patient outcomes as reported by health care professionals on case report forms.ResultsAmong 418 patients, median (IQR) age at the time of testing was 4 (1-10) years, with an age range of 0 to 52 years, and 53.8% (n = 225) were female individuals. The mean (SD) time from a genetic test order to case report form completion was 595 (368) days (range, 27-1673 days). A genetic diagnosis was associated with changes in clinical management for 208 patients (49.8%) and usually (81.7% of the time) within 3 months of receiving the result. The most common clinical management changes were the addition of a new medication (78 [21.7%]), the initiation of medication (51 [14.2%]), the referral of a patient to a specialist (48 [13.4%]), vigilance for subclinical or extraneurological disease features (46 [12.8%]), and the cessation of a medication (42 [11.7%]). Among 167 patients with follow-up clinical information available (mean [SD] time, 584 [365] days), 125 (74.9%) reported positive outcomes, 108 (64.7%) reported reduction or elimination of seizures, 37 (22.2%) had decreases in the severity of other clinical signs, and 11 (6.6%) had reduced medication adverse effects. A few patients reported worsening of outcomes, including a decline in their condition (20 [12.0%]), increased seizure frequency (6 [3.6%]), and adverse medication effects (3 [1.8%]). No clinical management changes were reported for 178 patients (42.6%).Conclusions and RelevanceResults of this cross-sectional study suggest that genetic testing of individuals with epilepsy may be materially associated with clinical decision-making and improved patient outcomes.

Adolescence is a sensitive developmental period for limbic and dopamine systems that coincides with the typical age for onset of tobacco use. We have previously shown that a 4-day, low-dose nicotine (0.06 mg/kg) pretreatment enhances locomotor and penile response to the D2-like agonist, quinpirole (0.4 mg/kg), in adolescent but not adult rats. The present study is designed to determine mechanisms underlying this effect. Nicotine enhancement of adolescent quinpirole-induced locomotion was mediated by D2 receptors (D2Rs) since it was blocked by the D2R antagonist, L-741,626, but not by the D3R and D4R antagonists, NGB 2904 and L-745,870. Enhancement of quinpirole-induced erectile response was blocked by both L-741,626 and NGB 2904, indicating involvement of D3Rs. Whereas D2R binding was unaffected by adolescent nicotine pretreatment, effector coupling in the striatum was increased, as determined by GTPγS binding. Nicotine pretreatment enhanced quinpirole-induced c-fos mRNA expression in the hypothalamic paraventricular and supraoptic nuclei in adolescents only. Adolescent nicotine pretreatment enhanced c-fos mRNA expression in corticotropin releasing factor (CRF) cells of the paraventricular nucleus, and enhancement of penile erection was blocked by the CRF-1 receptor antagonist, CP 376,396. These findings suggest that adolescent dopamine and CRF systems are vulnerable to alteration by nicotine. This is the first evidence for a role of CRF in adolescent erectile response.

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INTRODUCTION Moyamoya disease is a progressive cerebrovascular arteriopathy of unknown etiology, causing narrowing and eventual occlusion of the internal carotid arteries and their branches. Surgical revascularization is a key component of the overall treatment strategy. The goal of this study was to determine outcomes and complications related to direct vascular bypass in a pediatric cohort with Moyamoya disease. METHODS All pediatric patients (<18 yr of age) treated with direct bypass combined with encephalomyosynangiosis between 2006 and 2017 at the authors’ institution were included in the cohort. Demographic features, treatment, and outcomes were determined retrospectively from clinical reports available through the electronic medical record. RESULTS A total of 18 patients (11 females and 7 males) underwent 32 bypass procedures with a median follow-up of 2.2 yr (range 22 d 8.6 yr). Mean age at operation was 8.3 yr (range 1.4-16.9 yr). Preoperative Suzuki stage 1, 2, 3, 4, and 5 were seen in 2, 7, 7, 12, and 4 hemispheres, respectively. By last follow-up, 3 patients had evidence of new clinical ischemic stroke, all occurring within 30 d of surgery. Favorable outcomes (pediatric modified Rankin scores 0-2) at last follow-up were seen in 15 patients (83.3%). There was 1 death in the cohort due to gastrointestinal bleeding related to underlying medical comorbidities. On review of imaging at last follow-up for surviving patients, 29 of 30 direct arterial bypasses were patent; 12 and 5 patients had stable and worse imaging findings, respectively, when compared to immediate postoperative scans. CONCLUSION Combined direct and indirect revascularization procedures may be successfully applied to pediatric patients with Moyamoya disease of all age groups. The direct bypass component provides immediate revascularization and is associated with high rates of patency on follow-up imaging.