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Background: Adolescence is defined by key transitional elements which are considered within a cross-cultural context. The importance of building mental health capacity for adolescents in low- and middle-income countries (LMICs) as well as high-income countries (HICs) is reviewed. Objectives: To review the developmental period of adolescence, global needs for mental health promotion, the needs of LMICs while emphasizing building adolescent mental health capacity, and the importance of efforts to promote mental health literacy. Methods: Mental health literacy (MHL) is presented as a strategy that can increase public awareness regarding mental health issues among adolescents. Increased awareness through an MHL framework is discussed as a way to build adolescent mental health capacity; with this work ideally occurring through global communities of practice (COP), dialogue, collaboration, and mutual support that aim to build innovation in systems of mental health promotion. Results: The authors review structural components in research, practice, and policy that seek to build global adolescent mental health capacity, nested within COPs involving HICs and LMICs working together to advance mental health promotion for children, adolescents, and young people. Conclusion: The article concludes with a discussion of how the three structural components (i.e., research, practice, and policy) can address gaps in the provision of global mental health services for adolescents to meet adolescent mental health needs in LMICs and HICs. A multi-sectoral approach emphasizing a global COP is presented as a way to scale up capacity and maximize outcomes.

Resumen: Antecedentes y objetivos: La cistinosis es un error innato del metabolismo cuyas características clínicas incluyen compromiso renal severo y formación de cristales de cistina en la córnea, especialmente en la presentación adulta de la enfermedad. Es una enfermedad tratable, por lo cual establecer el diagnóstico de forma oportuna es fundamental para iniciar la terapia. Para la confirmación bioquímica de la enfermedad se requiere determinar las concentraciones intracelulares de cistina, para lo cual se han reportado diferentes métodos tanto para el aislamiento de las células como para la cuantificación del aminoácido. Con el objetivo de mejorar el diagnóstico bioquímico confirmatorio en nuestro medio establecimos un protocolo de cuantificación intraleucocitaria de cistina. Métodos: Se implementó un método de cuantificación de cistina en polimorfonucleares por cromatografía líquida de alta resolución, evaluando el mejor anticoagulante a utilizar, la estabilidad de la muestra a 4 ̊C y estableciendo valores de referencia para nuestra población. Resultados: Se determinó que la muestra para cuantificación intraleucocitaria de cistina debe ser anticoagulada mediante la adición de ácido cítrico-dextrosa como anticoagulante. La muestra debe ser procesada inmediatamente, dada su baja estabilidad incluso en refrigeración. Con 50 individuos sanos se estableció como punto de corte para nuestra población 0,34 nmol 1/2 cistina/mg. Conclusión: La adaptación realizada del método de cuantificación de cistina utiliza el número más alto de muestras control hasta ahora reportado en la literatura. Nuestros resultados dan cuenta de la necesidad de implementar el método a nivel local y reafirman la conveniencia de que cada laboratorio establezca sus propios valores de referencia para proporcionar una mayor confiabilidad a la hora de interpretar los resultados. Abstract: Background and aims: Cystinosis is an inborn error of metabolism, clinically characterised by severe renal involvement and development of corneal cystine deposits, especially in the adult form of the disease. Cystinosis is a treatable condition. Therefore, an early diagnosis is necessary to start therapy. For biochemical confirmation of the condition it is necessary to quantify intracellular cystine concentrations. For this, different methods have been described with variations in cell isolation strategies and the amino acid quantification techniques used. In order to improve confirmatory biochemical diagnosis in our setting, a protocol for intraleukocitary cystine quantification was established. Methods: A high performance liquid chromatography based method for cystine quantification in polymorphonuclear cells was implemented. Evaluation of the best anticoagulant to use and temperature stability of the sample at 4 ̊C were performed. In addition, we established reference values for our population. Results: It was determined that intraleukocitary cystine quantification must be performed in blood samples containing acid-citrate-dextrose as anticoagulant. Samples must be processed immediately due to their poor stability even when refrigerated. Based on the results from 50 healthy individuals, the cut-off point established for our population was 0.34 nmol 1/2 cystine/mg. Conclusion: The adaptation performed to the cystine quantification method here presented the highest control population that has been reported in the literature so far. Our results highlight the need for making available a cystine quantification method locally and confirm the convenience for each laboratory to establish its own reference values to provide greater reliability for interpreting results. Palabras clave: Cistinosis, Aminoacidopatía, Error innato del metabolismo, Cistina intraleucocitaria, Síndrome de Fanconi, Keywords: Cystinosis, Aminoacidopathy, Inborn error of metabolism, Intraleukocitary cystine, Fanconi syndrome

Background and aims: Cystinosis is an inborn error of metabolism, clinically characterised by severe renal involvement and development of corneal cystine deposits, especially in the adult form of the disease. Cystinosis is a treatable condition. Therefore, an early diagnosis is necessary to start therapy. For biochemical confirmation of the condition it is necessary to quantify intracellular cystine concentrations. For this, different methods have been described with variations in cell isolation strategies and the amino acid quantification techniques used. In order to improve confirmatory biochemical diagnosis in our setting, a protocol for intraleukocitary cystine quantification was established. Methods: A high performance liquid chromatography based method for cystine quantification in polymorphonuclear cells was implemented. Evaluation of the best anticoagulant to use and temperature stability of the sample at 4 °C were performed. In addition, we established reference values for our population. Results: It was determined that intraleukocitary cystine quantification must be performed in blood samples containing acid-citrate-dextrose (ACD) as anticoagulant. Samples must be processed immediately due to their poor stability even when refrigerated. Based on the results from 50 healthy individuals, the cut-off point established for our population was 0.34 nmol1/2/cystine/mg. Conclusion: The adaptation performed to the cystine quantification method here presented the highest control population that has been reported in the literature so far. Our results highlight the need for making available a cystine quantification method locally and confirm the convenience for each laboratory to establish its own reference values to provide greater reliability for interpreting results. Resumen: Antecedentes y objetivos: La cistinosis es un error innato del metabolismo cuyas características clínicas incluyen compromiso renal severo, formación de cristales de cistina en la córnea, especialmente en la presentación adulta de la enfermedad. Es una enfermedad tratable por lo cual establecer el diagnostico de forma oportuna es fundamental para iniciar terapia. Para la confirmación bioquímica de la enfermedad se requiere determinar las concentraciones intracelulares de cistina, para lo cual se han reportado diferentes métodos tanto para el aislamiento de las células como las técnicas de cuantificación del aminoácido. Con el objetivo de mejorar el diagnóstico bioquímico confirmatorio en nuestro medio establecimos un protocolo de cuantificación intraleucocitaria de cistina. Métodos: Se realizó implementación de un método de cuantificación de cistina en polimorfonucleares por cromatografía líquida de alta resolución, evaluando el mejor anticoagulante a utilizar, la estabilidad de la muestra a 4 °C y estableciendo valores de referencia para nuestra población. Resultados: Se determinó que la muestra para cuantificación intraleucocitaria de cistina debe ser anticoagulada mediante adición de ácido Cítrico-Dextrosa (ACD) como anticoagulante. La muestra debe ser procesada inmediatamente dada su baja estabilidad incluso en refrigeración. Con 50 individuos sanos se estableció como punto de corte para nuestra población 0.34 nmol1/2cistina/mg. Conclusión: La adaptación realizada del método de cuantificación de cistina utiliza el número más alto de muestras control hasta ahora reportado en la literatura. Nuestros resultados dan cuenta de la necesidad de implementar el método a nivel local y reafirman la conveniencia de que cada laboratorio establezca sus propios valores de referencia para proporcionar una mayor confiabilidad a la hora de interpretar los resultados. Keywords: Cystinosis, Aminoacidopathy, Inborn error of metabolism, Intraleukocitary cystine, Fanconi syndrome., Palabras clave: Cistinosis, Aminoacidopatia, Error innato del metabolismo, Cistina intraleucocitaria, Síndrome de fanconi

El síndrome de Leigh (SL) es una enfermedad neurodegenerativa, descrita como una encefalomielopatía necrotizante subaguda, y es una de las enfermedades de origen mitocondrial más frecuentes. El SL es causado por el déficit en la producción de energía, originada en defectos en los genes que codifican alguno de los complejos mitocondriales; el gen afectado puede ser de codificación tanto nuclear como mitocondrial, lo que explica que se encuentren diferentes mecanismos de herencia, incluyendo autosómica recesiva y herencia materna, lo que, a su vez, hace más difícil su diagnóstico molecular. Clínicamente se presenta con regresión del desarrollo cognitivo y pérdida de habilidades motoras con trastorno de movimiento, de rápida progresión. El diagnóstico se basa en la demostración bioquímica de la elevación del ácido láctico y de la relación lactato/piruvato, así como hallazgos en las neuroimágenes por resonancia magnética que muestran lesiones focales, bilaterales y simétricas en ganglios basales o tallo cerebral asociadas a leucoencefalopatía y atrofia cerebral. Se reportan cinco casos con diagnóstico clínico y bioquímico del SL que ejemplifican la variabilidad clínica y gravedad encontrada en este grupo de pacientes.

Although breast milk is the ideal food source for newborns during the first six months of life, a high percentage of children receive infant formulas. There is evidence that specific diet habits may influence individual metabolic profile. Therefore, in newborns, such profile can be influenced by the use of infantile formulas given the composition differences that display compared to human milk. Up to now, there are no reports in the literature that address this issue.this work aims to compare the metabolic profile of full-term newborns that were feed with either breast milk (n = 32) or infantile formulas (n = 21). Methods: Metabolic profile was established based on urine analysis through gas chromatography-mass spectrometry (GC-MS) and nuclear magnetic resonance (H-NMR).our results evidenced a more gluconeogenic profile in breast-fed infants characterized by elevation of Kreb's cycle intermediaries like fumaric, succinic and ketoglutaric acids compared to infants receiving infant formula. In addition, infant formula fed infants presented urinary excretion of metabolites derived from specific compounds present in this type of diet that were not observed in breast-fed infants, for instance D-glucitol, and 4-deoxytetronic. Moreover, in infant formula fed infants there was excretion of basal levels of metabolites of clinical relevance like 3-hydroxy-3-methyl-glutaric, 2-methyl-3-keto-valeric and 3,4-dihydroxybutyric.These results show the importance of understanding the metabolic impact of diet in newborn population in normal and pathological contexts.

Summary Background Bedaquiline and delamanid are the first drugs of new classes registered for tuberculosis treatment in 40 years. Each can prolong the QTc interval, with maximum effects occurring weeks after drug initiation. The cardiac safety and microbiological activity of these drugs when co-administered are not well-established. Our aim was to characterise the effects of bedaquiline, delamanid, or both on the QTc interval, longitudinally over 6 months of multidrug treatment, among patients with multidrug-resistant or rifampicin-resistant tuberculosis taking multidrug background therapy. Methods ACTG A5343 is a phase 2, open-label, randomised, controlled trial in which adults with multidrug-resistant or rifampicin-resistant tuberculosis receiving multidrug background treatment were randomly assigned 1:1:1 by centrally, computer-generated randomisation, by means of permuted blocks to receive bedaquiline, delamanid, or both for 24 weeks. Participants were enrolled at TASK in Cape Town and the South African Tuberculosis Vaccine Initiative in Worcester, both in South Africa, and Hospital Maria Auxiliadora in Peru. Individuals with QTc greater than 450 ms were excluded. HIV-positive participants received dolutegravir-based antiretroviral therapy. Clofazimine was disallowed, and levofloxacin replaced moxifloxacin. ECG in triplicate and sputum cultures were done fortnightly. The primary endpoint was mean QTcF change from baseline (averaged over weeks 8–24); cumulative culture conversation at week 8-24 was an exploratory endpoint. Analyses included all participants who initiated study tuberculosis treatment (modified intention-to-treat population). This trial is registered with ClinicalTrials.gov , NCT02583048 and is ongoing. Findings Between Aug 26, 2016 and July 13, 2018, of 174 screened, 84 participants (28 in each treatment group, and 31 in total with HIV) were enrolled. Two participants did not initiate study treatment (one in the delamanid group withdrew consent and one in the bedaquiline plus delamanid group) did not meet the eligibility criterion). Mean change in QTc from baseline was 12·3 ms (95% CI 7·8–16·7; bedaquiline), 8·6 ms (4·0–13·1; delamanid), and 20·7 ms (16·1–25·3) (bedaquiline plus delamanid). There were no grade 3 or 4 adverse QTc prolongation events and no deaths during study treatment. Cumulative culture conversion by week 8 was 21 (88%) of 24 (95% CI 71–97; bedaquiline), 20 (83%) of 24 (65–95; delamanid), and 19 (95%) of 20 (79–100; bedaquiline plus delamanid) and was 92% (77–99) for bedaquiline, 91% (76–99), for delamanid, and 95% (79–100) for bedaquiline plus delamanid at 24 weeks. Interpretation Combining bedaquiline and delamanid has a modest, no more than additive, effect on the QTc interval, and initial microbiology data are encouraging. This study provides supportive evidence for use of these agents together in patients with multidrug-resistant or rifampicin-resistant tuberculosis with normal baseline QTc values. Funding Division of AIDS, National Institutes of Health.

Background: Mucopolysaccharidoses (MPS) are a group of inherited metabolic diseases caused by impaired function or absence of lysosomal enzymes involved in degradation of glycosaminoglycans. Clinically, MPS are skeletal dysplasias, characterized by cartilage abnormalities and disturbances in the process of endochondral ossification. Histologic abnormalities of growth cartilage have been reported at advanced stages of the disease, but information regarding growth plate pathology progression either in humans or in animal models, as well as its pathophysiology, is limited. Methods: Histological analyses of distal femur growth plates of wild type (WT) and mucopolysaccharidosis type VI (MPS VI) rats at different stages of development were performed, including quantitative data. Experimental findings were then analyzed in a theoretical scenario. Results: Histological evaluation showed a progressive loss of histological architecture within the growth plate. Furthermore, in silico simulation suggest the abnormal cell distribution in the tissue may lead to alterations in biochemical gradients, which may be one of the factors contributing to the growth plate abnormalities observed, highlighting aspects that must be the focus of future experimental works. Conclusion: The results presented shed some light on the progression of growth plate alterations observed in MPS VI and evidence the potentiality of combined theoretical and experimental approaches to better understand pathological scenarios, which is a necessary step to improve the search for novel therapeutic approaches.

Background: This exploratory analysis was conducted to characterize the level of HPV types 6/11 antibodies in peripartum maternal blood and in cord blood of infants born to women who received 9-valent HPV (9vHPV) vaccine or quadrivalent HPV (qHPV) vaccine in a pivotal efficacy study (V503-001, NCT 00543543). Methods: A total of 21 mother-infant pairs had evaluable HPV 6/11 results available for analysis. HPV6/11 antibodies were assessed using competitive Luminex immunoassay. The distribution of the ratios of infant to mother anti-HPV antibodies (i.e., infant-anti-HPV/mother- anti-HPV) was summarized. Results: All mothers and infants were seropositive to HPV 6 and HPV 11. Anti-HPV 6/11 geometric mean titers (GMTs) in peripartum maternal blood and in cord blood of infant born to study participants were highly correlated. A 100% of infants born to seropositive mothers were also seropositive. The GMT ratios of peripartum maternal blood vs. those in cord blood were HPV 6: 1.23 [0.43, 3.49] and HPV 11: 1.29 [0.54, 3.07] in the 9vHPV vaccine group and HPV 6: 1.33 [0.41, 4.29] and HPV 11: 1.19 [0.45, 3.13] in the qHPV vaccine group, respectively. Conclusions: These results indicate that antibodies induced by the 9vHPV vaccine cross the placenta, which could potentially be beneficial against HPV6/11 infection and related disease such as recurrent respiratory papillomatosis.

Background: A 9-valent human papillomavirus (HPV6/11/16/18/31/33/45/52/58; 9vHPV) vaccine was developed to expand coverage of the previously developed quadrivalent (HPV6/11/16/18; qHPV) vaccine. Methods: Efficacy, immunogenicity, and safety outcomes were assessed in Latin American participants enrolled in 2 international studies of the 9vHPV vaccine, including a randomized, double-blinded, controlled with qHPV vaccine, efficacy, immunogenicity, and safety study in young women aged 16–26 years, and an immunogenicity and safety study in girls and boys aged 9–15 years. Participants (N=5312) received vaccination at Day 1, Month 2, and Month 6. Gynecological swabs were collected regularly in young women for cytological and HPV DNA testing. Serum was analyzed for HPV antibodies in all participants. Adverse events (AEs) were also monitored in all participants. Results: The 9vHPV vaccine prevented HPV 31-, 33-, 45-, 52-, and 58-related high-grade cervical, vulvar, and vaginal dysplasia with 92.3% efficacy (95% confidence interval 54.4, 99.6). Anti-HPV6, 11, 16, and 18 geometric mean titers at Month 7 were similar in the 9vHPV and qHPV vaccination groups. Anti-HPV antibody responses following vaccination were higher among girls and boys than in young women. Most (>99%) 9vHPV vaccine recipients seroconverted for all 9 HPV types at Month 7. Antibody responses to the 9 HPV types persisted over 5 years. The most common AEs were injection-site related, mostly of mild to moderate intensity. Conclusions: The 9vHPV vaccine is efficacious, immunogenic, and well tolerated in Latin American young women, girls, and boys. These data support 9vHPV vaccination programs in Latin America, a region with substantial cervical cancer burden. Keywords: Human papillomavirus, Vaccine, Cervical cancer, Persistent infection, 9vHPV

Cystinosis is an inborn error of metabolism, clinically characterised by severe renal involvement and development of corneal cystine deposits, especially in the adult form of the disease. Cystinosis is a treatable condition. Therefore, an early diagnosis is necessary to start therapy. For biochemical confirmation of the condition it is necessary to quantify intracellular cystine concentrations. For this, different methods have been described with variations in cell isolation strategies and the amino acid quantification techniques used. In order to improve confirmatory biochemical diagnosis in our setting, a protocol for intraleukocitary cystine quantification was established.A high performance liquid chromatography based method for cystine quantification in polymorphonuclear cells was implemented. Evaluation of the best anticoagulant to use and temperature stability of the sample at 4̊C were performed. In addition, we established reference values for our population.It was determined that intraleukocitary cystine quantification must be performed in blood samples containing acid-citrate-dextrose as anticoagulant. Samples must be processed immediately due to their poor stability even when refrigerated. Based on the results from 50 healthy individuals, the cut-off point established for our population was 0.34nmol 1/2 cystine/mg.The adaptation performed to the cystine quantification method here presented the highest control population that has been reported in the literature so far. Our results highlight the need for making available a cystine quantification method locally and confirm the convenience for each laboratory to establish its own reference values to provide greater reliability for interpreting results.

Background The 9-valent HPV (9vHPV) vaccine was developed to prevent infection and disease related to 9 HPV types (HPV6/11/16/18/31/33/45/52/58) which cause approximately 90% of cervical cancers, HPV-related vulvar, vaginal and anal cancers, and genital warts worldwide. In a pivotal efficacy study, the 9vHPV vaccine prevented infection and disease due to the 9 vaccine types. Duration of protection remains to be determined. Vaccines that induce long-term protection are generally characterized by the generation of immune memory. The purpose of this report is to assess the persistence of HPV antibody response and existence of immune memory at 5 years post-vaccination. Methods A subset of subjects (N = 150) who received 3 doses of 9vHPV vaccine at day 1, month 2 and month 6 in the pivotal efficacy study continued in a study extension and received a fourth dose of 9vHPV vaccine at month 60. Serum HPV antibody levels were measured pre-dose 4 and at 7 and 28 days post-dose 4 by competitive Luminex immunoassay. Adverse events were assessed using a vaccination report card. Results HPV antibodies induced following the 3-dose series of 9vHPV vaccine in the base study persisted through month 60 with seropositivity rates ranging from 77.5% to 100%. Geometric mean titers at 1 week and 1 month post-dose 4 were 1.25–4.10 and 1.65–4.88-fold higher, respectively, than levels observed 1 month following the completion of the three-dose primary series. Seropositivity rates were >99% and 100% at 1 week and 1 month post-dose 4, respectively. The fourth dose of 9vHPV vaccine was generally well tolerated. Conclusions A three-dose regimen of the 9vHPV vaccine induced persistent HPV antibody response through 5 years post-vaccination. Administration of a fourth dose resulted in a strong anamnestic response to all 9 vaccine types. These findings suggest that the efficacy of the 9vHPV vaccine will be long lasting. Clinical Trials.gov Identifier: NCT00543543 .

Background Breast cancer is one of the most prevalent malignancies in the world. In Peru, breast cancer is the second cause of death among women. Five to ten percent of patients present a high genetic predisposition due to BRCA1 and BRCA2 germline mutations. Methods We performed a comprehensive analysis of BRCA1 and BRCA2 genes by Sanger sequencing and multiplex ligation‐dependent probe amplification (MLPA) to detect large rearrangements in patients from 18 families, which met the criteria for hereditary breast cancer. Results In this series, we found four pathogenic mutations, three previously reported (BRCA1: c.302‐1G>C and c.815_824dup10; BRCA2: c.5946delT) and a duplication of adenines in exon 15 in BRCA1 gene (c.4647_4648dupAA, ClinVar SCV000256598.1). We also found two exonic and four intronic variants of unknown significance and 28 polymorphic variants. Conclusion This is the first report to determine the spectrum of mutations in the BRCA1/BRCA2 genes in Peruvian families selected by clinical and genetic criteria. The alteration rate in BRCA1/BRCA2 with proven pathogenic mutation was 22.2% (4 out 18) and this finding could be influenced by the reduced sample size or clinical criteria. In addition, we found three known BRCA1/BRCA2 mutations and a BRCA1 c.4647_4648dupAA as a novel pathogenic mutation.

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Utilizing postmortem data (Breese et al. [2000] Neuropsychopharmacology 23:351-364), we hypothesized that the densities of high-affinity neuronal α4β2 nicotinic acetylcholine receptors (nAChRs) in the brain exist in a continuum from highest to lowest as follows: smokers without schizophrenia > smokers with schizophrenia > nonsmokers without schizophrenia > nonsmokers with schizophrenia. Application of the Kruskal-Wallis Test (Statacorp, 2003) to the postmortem data (Breese et al. [2000] Neuropsychopharmacology 23:351-364) confirmed the hypothesized order in the cortex and the hippocampus and attained significance in the caudate and the thalamus. Positron emission tomography (PET) was performed for 60 min at 6 h after the intravenous administration of 444 megabequerels [MBq] (12 mCi) 2-[¹⁸F]fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2-[¹⁸F]FA), a radiotracer for high-affinity neuronal α4β2 nAChRs, as a bolus plus continuous infusion to 10 adults (seven men and three women) (six smokers including five with paranoid schizophrenia and four nonsmokers) ranging in age from 22 to 56 years (mean 40.1, standard deviation 13.6). The thalamic nondisplaceable binding potential (BP(ND) ) was 1.32 ± 0.19 (mean ± standard deviation) for healthy control nonsmokers; 0.50 ± 0.19 for smokers with paranoid schizophrenia; and 0.51 for the single smoker without paranoid schizophrenia. The thalamic BP(ND) s of nonsmokers were significantly higher than those of smokers who smoked cigarettes a few hours before the scans (P = 0.0105) (StataCorp, 2003), which was likely due to occupancy of nAChRs by inhaled nicotine in smokers. Further research is needed to rule out the effects of confounding variables.

Central modulation of serotonin and dopamine underlies efficacy for a variety of psychiatric therapeutics. ITI-007 is an investigational new drug in development for treatment of schizophrenia, mood disorders, and other neuropsychiatric disorders.The purpose of this study was to determine brain occupancy of ITI-007 at serotonin 5-HT2A receptors, dopamine D2 receptors, and serotonin transporters using positron emission tomography (PET) in 16 healthy volunteers.Carbon-11-MDL100907, carbon-11-raclopride, and carbon-11-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile) (carbon-11-DASB) were used as the radiotracers for imaging 5-HT2A receptors, D2 receptors, and serotonin transporters, respectively. Brain regions of interest were outlined using magnetic resonance tomography (MRT) with cerebellum as the reference region. Binding potentials were estimated by fitting a simplified reference tissue model to the measured tissue-time activity curves. Target occupancy was expressed as percent change in the binding potentials before and after ITI-007 administration.Oral ITI-007 (10-40 mg) was safe and well tolerated. ITI-007 rapidly entered the brain with long-lasting and dose-related occupancy. ITI-007 (10 mg) demonstrated high occupancy (80 %) of cortical 5-HT2A receptors and low occupancy of striatal D2 receptors (~12 %). D2 receptor occupancy increased with dose and significantly correlated with plasma concentrations (r (2) = 0.68, p = 0.002). ITI-007 (40 mg) resulted in peak occupancy up to 39 % of striatal D2 receptors and 33 % of striatal serotonin transporters.The results provide evidence for a central mechanism of action via dopaminergic and serotonergic pathways for ITI-007 in living human brain and valuable information to aid dose selection for future clinical trials.

Rett syndrome (RTT) is a neurodevelopmental disability characterized by mutations in the X-linked methyl-CpG-binding protein 2 located at the Xq28 region. The severity is modified in part by X chromosomal inactivation resulting in wide clinical variability. We hypothesized that the ability to perform the activities of daily living (ADL) is correlated with the density of vesicular acetylcholine transporters in the striata of women with RTT. The density of the vesicular acetylcholine transporters in the living human brain can be estimated by single-photon emission-computed tomography (SPECT) after the administration of (−)-5-[123I]iodobenzovesamicol ([123I]IBVM). Twenty-four hours following the intravenous injection of ∼333 MBq (9 mCi) [123I]IBVM, four women with RTT and nine healthy adult volunteer control participants underwent SPECT brain scans for 60 min. The Vesicular Acetylcholine Transporter Binding Site Index (Kuhl et al., 1994), a measurement of the density of vesicular acetylcholine transporters, was estimated in the striatum and the reference structure, the cerebellum. The women with RTT were assessed for certain ADL. Although the striatal Vesicular Acetylcholine Transporter Binding Site Index was not significantly lower in RTT (5.2 ± 0.9) than in healthy adults (5.7 ± 1.6), RTT striatal Vesicular Acetylcholine Transporter Binding Site Indices and ADL scores were linearly associated (ADL = 0.89*(Vesicular Acetylcholine Transporter Binding Site Index) + 4.5; R2 = 0.93; P < 0.01), suggesting a correlation between the ability to perform ADL and the density of vesicular acetylcholine transporters in the striata of women with RTT. [123I]IBVM is a promising tool to characterize the pathophysiological mechanisms of RTT and other neurodevelopmental disabilities. Synapse, 2012. © 2011 Wiley Periodicals, Inc.

Several studies have examined the link between the cannabinoid CB1 receptor and several neuropsychiatric illnesses, including schizophrenia. As such, there is a need for in vivo imaging tracers so that the relationship between CB1 and schizophrenia (SZ) can be further studied. In this paper, we present our first human studies in both healthy control patients and patients with schizophrenia using the novel PET tracer, [(11)C]OMAR (JHU 75528), we have shown its utility as a tracer for imaging human CB1 receptors and to investigate normal aging and the differences in the cannabinoid system of healthy controls versus patients with schizophrenia. A total of ten healthy controls and nine patients with schizophrenia were included and studied with high specific activity [(11)C]OMAR. The CB1 binding (expressed as the distribution volume; V(T)) was highest in the globus pallidus and the cortex in both controls and patients with schizophrenia. Controls showed a correlation with the known distribution of CB1 and decline of [(11)C]OMAR binding with age, most significantly in the globus pallidus. Overall, we observed elevated mean binding in patients with schizophrenia across all regions studied, and this increase was statistically significant in the pons (p

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