Should we offer prenatal testing for 17q12 microdeletion syndrome to all cases with prenatally diagnosed echogenic kidneys? Prenatal findings in two families with 17q12 microdeletion syndrome and review of the literature.

OBJECTIVE: The objective of this study is to report the prenatal ultrasound scan findings in four fetuses from two families postnatally diagnosed with 17q12 microdeletion syndrome on microarray CGH and review the literature. METHODS: We report two families presenting with prenatally detected hyperechogenic kidneys. In family 1, the mother had three pregnancies complicated by anhydramnios with bilateral hyperechogenic kidneys, hyperechogenic enlarged cystic kidneys, and bilateral hyperechogenic kidneys with polyhydramnios respectively. In family 2, prenatal ultrasound scans detected hyperechogenic kidneys. A pubmed search for all reported cases of 17q12 deletion between 2005 and 2015 was performed. All publications were reviewed, and findings summarised. RESULTS: Fourteen publications were deemed suitable for literature review; there was a diagnosis of 17q12 deletion with documented prenatal findings in 25 cases. Prenatal renal anomalies were reported in 88% of these cases. Anomalies were documented from 15 weeks, and most common presentation was hyperechogenic, muticystic, or enlarged kidneys. Both oligohydramnios and polyhydramnios were seen. Postnatal renal ultrasound scan findings were of muticystic or multicystic dysplastic kidney. There did not appear to be correlation of prenatal presentation and severity of renal disease. CONCLUSION: Prenatal testing should be offered to all cases of hyperechogenic kidneys, with unknown cause.

Effects of the DPP-4 inhibitor, linagliptin, in diet-induced obese rats: a comparison in naive and exenatide-treated animals.

BACKGROUND: To assess the chronic effect of the DPP-4 inhibitor, linagliptin, alone, in combination with exenatide, and during exenatide withdrawal, in diet-induced obese (DIO) rats. METHODS: Female Wistar rats were exposed to a cafeteria diet to induce obesity. Animals were then dosed with vehicle or linagliptin (3 mg/kg PO) orally once-daily for a 28 day period. In a subsequent study, rats received exenatide (either 3 or 30 microg/kg/day) or vehicle by osmotic mini-pump for 28 days. In addition, groups of animals were dosed orally with linagliptin either alone or in combination with a 3 microg/kg/day exenatide dose for the study duration. In a final study, rats were administered exenatide (30 microg/kg/day) or vehicle by osmotic mini-pump for eleven days. Subsequently, exenatide-treated animals were transferred to vehicle or continued exenatide infusion for a further ten days. Animals transferred from exenatide to vehicle were also dosed orally with either vehicle or linagliptin. In all studies, body weight, food and water intake were recorded daily and relevant plasma parameters and carcass composition were determined. RESULTS: In contrast to exenatide, linagliptin did not significantly reduce body weight or carcass fat in DIO rats versus controls. Linagliptin augmented the effect of exenatide to reduce body fat when given in combination but did not affect the body weight response. In rats withdrawn from exenatide, weight regain was observed such that body weight was not significantly different to controls. Linagliptin reduced weight regain after withdrawal of exenatide such that a significant difference from controls was evident. CONCLUSIONS: These data demonstrate that linagliptin does not significantly alter body weight in either untreated or exenatide-treated DIO rats, although it delays weight gain after exenatide withdrawal. This finding may suggest the utility of DPP-4 inhibitors in reducing body weight during periods of weight gain.

Novel, non-nitrocatechol catechol-O-methyltransferase inhibitors modulate dopamine neurotransmission in the frontal cortex and improve cognitive flexibility.

RATIONALE: Cognitive impairment is a primary feature of many neuropsychiatric disorders and there is a need for new therapeutic options. Catechol-O-methyltransferase (COMT) inhibitors modulate cortical dopaminergic function and have been proposed as potential cognitive enhancers. Unfortunately, currently available COMT inhibitors are not good candidates due to either poor blood-brain barrier penetration or severe toxicity. OBJECTIVES: To address the need for safe, brain-penetrant COMT inhibitors, we tested multiple novel compounds in a set of preclinical in vivo efficacy assays in rats to determine their ability to inhibit COMT function and viability as potential clinical candidates. METHODS: We measured the change in concentration of dopamine (DA) metabolites in cerebrospinal fluid (CSF) from the cisterna magna and extracellular fluid (ECF) from the frontal cortex produced by our novel compounds. Additionally, we tested the effects of our brain-penetrant COMT inhibitors in an attentional set-shifting assay (ASST). We benchmarked the performance of the novel COMT inhibitors to the effects produced by the known COMT inhibitor tolcapone. RESULTS: We found that multiple COMT inhibitors, exemplified by LIBD-1 and LIBD-3, significantly modulated dopaminergic function measured as decreases in homovanillic acid (HVA) and increases in 3,4-Dihydroxyphenylacetic acid (DOPAC), two DA metabolites, in CSF and the frontal cortex. Additionally, we found that LIBD-1 significantly improved cognitive flexibility in the ASST, an effect previously reported following tolcapone administration. CONCLUSIONS: These results demonstrate that LIBD-1 is a novel COMT inhibitor with promising in vivo activity and the potential to serve as a new therapy for cognitive impairment.

Comparison of the effects of bupropion and nicotine on locomotor activation and dopamine release in vivo.

Bupropion is an atypical anti-depressant that is approved for smoking cessation. In addition to inhibiting dopamine reuptake, bupropion has been reported to block nicotinic acetylcholine receptors in vitro, and this action might contribute to its efficacy for smoking cessation. In this study we investigated if nicotinic receptor-mediated responses in vivo are decreased in the presence of a behaviorally effective dose of bupropion. In separate experiments we measured locomotor activation and dopamine overflow in the nucleus accumbens core, using in vivo microdialysis in freely moving rats. Bupropion (30 mg/kg i.p.) increased locomotor activity, which remained elevated for up to 2 h. Nicotine (0.4 mg/kg s.c.) also increased locomotor activity but for a shorter duration. When given 20 min after bupropion, hyperlocomotion was significantly enhanced, compared to the response to either nicotine or bupropion alone, consistent with the effects of the two drugs being additive. Systemic administration of bupropion (30 mg/kg i.p.) also elicited a significant increase in dopamine overflow (113+/-16% above basal levels). Nicotine (3 mM; delivered into the nucleus accumbens core via the microdialysis probe) increased dopamine overflow by 126 +/- 35%. Nicotine delivered during the response to bupropion resulted in enhanced dopamine overflow of 294 +/- 50%, also consistent with the actions of the two drugs being additive. This study suggests that behaviorally effective concentrations of bupropion in the rat do not diminish the effects of nicotine by blocking nicotinic receptors.

Determination of Injury Risks and Safety Measures Taken by Mothers of Children With an Intellectual Disability and Autism Spectrum Disorder.

PURPOSE: The purpose of the study is to determine the injury risk behaviors and home safety measures in children with an intellectual disability or autism spectrum disorder. METHOD: The study sample included mothers of 100 children between the ages of 2 and 12 years. FINDINGS: There was a significant difference between the home safety measures and the children's ages, the birth order of the children, and the mother's and father's ages. There was not a significant relationship between the children's ages, diagnosis, and Injury Behavior Checklist (IBC). There is a positive correlation between the total score of the Home Safety Measures Control List and IBC.

The effects in rats of lisdexamfetamine in combination with olanzapine on mesocorticolimbic dopamine efflux, striatal dopamine D2 receptor occupancy and stimulus generalization to a D-amphetamine cue.

The etiology of schizophrenia is poorly understood and two principle hypotheses have dominated the field. Firstly, that subcortical dopamine function is enhanced while cortical dopamine function is reduced and secondly, that cortical glutamate systems are dysfunctional. It is also widely accepted that currently used antipsychotics have essentially no impact on cognitive deficits and persistent negative symptoms in schizophrenia. Reduced dopamine transmission via dopamine D1 receptors in the prefrontal cortex has been hypothesized to be involved in the aetiology of these symptom domains and enhancing cortical dopamine transmission within an optimal window has been suggested to be potentially beneficial. In these pre-clinical studies we have determined that combined administration of the d-amphetamine pro-drug, lisdexamfetamine and the atypical antipsychotic olanzapine increased dopamine efflux in the rat prefrontal cortex and nucleus accumbens to an extent greater than either drug given separately without affecting olanzapine's ability to block striatal dopamine D2 receptors which is important for its antipsychotic activity. Furthermore, in an established rodent model used to compare the subjective effects of novel compounds the ability of lisdexamfetamine to generalize to a d-amphetamine cue was dose-dependently attenuated when co-administered with olanzapine suggesting that lisdexamfetamine may produce less marked subjective effects when administered adjunctively with olanzapine.

Differences in the neurochemical and behavioural profiles of lisdexamfetamine methylphenidate and modafinil revealed by simultaneous dual-probe microdialysis and locomotor activity measurements in freely-moving rats.

Lisdexamfetamine dimesylate is a novel prodrug approved in North America, Europe and Brazil for treating attention deficit hyperactivity disorder (ADHD). It undergoes rate-limited hydrolysis by red blood cells to yield d-amphetamine. Following our previous work comparing lisdexamfetamine with d-amphetamine, the neurochemical and behavioural profiles of lisdexamfetamine, methylphenidate and modafinil were compared by dual-probe microdialysis in the prefrontal cortex (PFC) and striatum of conscious rats with simultaneous locomotor activity measurement. We employed pharmacologically equivalent doses of all compounds and those that spanned the therapeutically relevant and psychostimulant range. Lisdexamfetamine (0.5, 1.5, 4.5 mg/kg d-amphetamine base, per os (po)), methylphenidate (3, 10, 30 mg/kg base, po) and modafinil (100, 300, 600 mg/kg base, po) increased efflux of dopamine and noradrenaline in PFC, and dopamine in striatum. Only lisdexamfetamine increased 5-hydroxytryptamine (5-HT) efflux in PFC and striatum. Lisdexamfetamine had larger and more sustained effects on catecholaminergic neurotransmission than methylphenidate or modafinil. Linear correlations were observed between striatal dopamine efflux and locomotor activity for lisdexamfetamine and methylphenidate, but not modafinil. Regression slopes revealed greater increases in extracellular dopamine could be elicited without producing locomotor activation by lisdexamfetamine than methylphenidate. These results are consistent with clinical findings showing that lisdexamfetamine is an effective ADHD medication with prolonged duration of action and good separation between its therapeutic actions and stimulant side-effects.

Obesidade e hipertensão em adolescentes e adultos com deficiência intelectual / Obesity and hypertension in adolescents and adults with intellectual disability

Resumo Objetivo O objetivo deste estudo foi identificar as taxas de obesidade e hipertensão arterial em indivíduos com deficiência intelectual. Métodos Este estudo foi realizado com adolescentes e adultos com deficiência intelectual em três centros emIzmir, Turquia. O IMC dos adultos foi determinado de acordo com o Programa de Prevenção e Controle da obesidade da Turquia. O IMC dos adolescentes foi avaliado de acordo com as curvas de percentis de IMC para crianças turcas. Para a avaliação dos níveis de pressão arterial de adultos, foi utilizado o sistema de classificação determinado pela Sociedade Turca de Cardiologia. O diagnóstico da pressão sanguínea em adolescentes é diferente dos adultos. Em termos de idade e sexo, pressões arteriais sistólica e diastólica menores que o percentil 90 são considerados normais. Resultados Os valores médios dos adultos foram: altura de 166 ± 0,1 cm, peso de 71,7 ± 1,86 kg, pressão arterial sistólica de 120,8 ± 1,53 mmHg, pressão arterial diastólica de 74,8 ± 1,35 mmHg e IMC de 25,96 ± 5,98. Os valores médios dos adolescentes foram: IMC de 23,02 ± 6,3, pressão arterial sistólica de 117 ± 14,3 mmHg e diastólica de 70 ± 13,8 mmHg. Dentre os adultos, 37,3% estavam com peso normal e 28% estavam acima do peso. A análise do IMC dos adolescentes demonstrou que 46,1% estavam entre o 5ª e 85º percentis, 26,3% encontravam-se acima do percentil 95 e 18,4% estavam abaixo do 5º percentil. Dentre os adultos, 59,8% tinham pressão sistólica ótima e 77,5% tinham pressão diastólica ótima. Conclusão Os resultados deste estudo demonstram que as taxas de obesidade e hipertensão é elevada em adolescentes e adultos com deficiência intelectual e, portanto, estes indivíduos encontram-se em sério risco de desenvolver doença cardiovascular.

Abstract Objective The aim of this study is to determine the rate of obesity and hypertension in individuals with intellectual disability. Methods This study was carried out with the adolescents and adults with intellectual disability in three centres, in Izmir, Turkey. The BMI of the adults were classified according to the Turkey Obesity Prevention and Control Program. The BMIs of the adolescents were evaluated according to the BMI percentile curves for Turkish children. For the evaluation of blood pressure levels of adults, the classification system determined by the Turkish Society of Cardiology was used. Blood pressure diagnosis in adolescents is different from that in adults. In terms of age and gender, systolic and diastolic blood pressures lower than the 90th percentile are considered as normal. Results The mean measurements for adults were as follows: height 166 ± 0.1 cm, weight 71.7 ± 1.86 kg, systolic blood pressure 120.8 ± 1.53 mmHg, diastolic blood pressure 74.8 ± 1.35 mmHg, and BMI 25.96 ± 5.98. The mean measurements for adolescents were as follows: BMI 23.02 ± 6.3 systolic blood pressure 117 ± 14.3 mmHg and diastolic pressure 70 ± 13.8 mmHg. 37.3% of adults were of normal weight and 28% were overweight. Analysis of BMI of the adolescents demonstrated that 46.1% were between the 5th and 85th percentiles, 26.3% appeared above the 95th percentile and 18.4% were below the 5th percentile. Of the subjects, 59.8% had an optimal systolic pressure and 77.5% had an optimal diastolic pressure of adults. Conclusion The results of this study demonstrate that the rate of obesity and hypertension is high in adolescents and adults with intellectual disabilities and therefore, these individuals are at a serious risk of developing cardiovascular disease.