Molecular Rescue of Dyrk1A Overexpression Alterations in Mice with Fontup® Dietary Supplement: Role of Green Tea Catechins.

Epigallocatechin gallate (EGCG) is an inhibitor of DYRK1A, a serine/threonine kinase considered to be a major contributor of cognitive dysfunctions in Down syndrome (DS). Two clinical trials in adult patients with DS have shown the safety and efficacy to improve cognitive phenotypes using commercial green tea extract containing EGCG (45% content). In the present study, we performed a preclinical study using FontUp®, a new nutritional supplement with a chocolate taste specifically formulated for the nutritional needs of patients with DS and enriched with a standardized amount of EGCG in young mice overexpressing Dyrk1A (TgBACDyrk1A). This preparation is differential with previous one used, because its green tea extract has been purified to up 94% EGCG of total catechins. We analyzed the in vitro effect of green tea catechins not only for EGCG, but for others residually contained in FontUp®, on DYRK1A kinase activity. Like EGCG, epicatechin gallate was a noncompetitive inhibitor against ATP, molecular docking computations confirming these results. Oral FontUp® normalized brain and plasma biomarkers deregulated in TgBACDyrk1A, without negative effect on liver and cardiac functions. We compared the bioavailability of EGCG in plasma and brain of mice and have demonstrated that EGCG had well crossed the blood-brain barrier.

Prenatal treatment with EGCG enriched green tea extract rescues GAD67 related developmental and cognitive defects in Down syndrome mouse models.

Down syndrome is a common genetic disorder caused by trisomy of chromosome 21. Brain development in affected foetuses might be improved through prenatal treatment. One potential target is DYRK1A, a multifunctional kinase encoded by chromosome 21 that, when overexpressed, alters neuronal excitation-inhibition balance and increases GAD67 interneuron density. We used a green tea extract enriched in EGCG to inhibit DYRK1A function only during gestation of transgenic mice overexpressing Dyrk1a (mBACtgDyrk1a). Adult mice treated prenatally displayed reduced levels of inhibitory markers, restored VGAT1/VGLUT1 balance, and rescued density of GAD67 interneurons. Similar results for gabaergic and glutamatergic markers and interneuron density were obtained in Dp(16)1Yey mice, trisomic for 140 chromosome 21 orthologs; thus, prenatal EGCG exhibits efficacy in a more complex DS model. Finally, cognitive and behaviour testing showed that adult Dp(16)1Yey mice treated prenatally had improved novel object recognition memory but do not show improvement with Y maze paradigm. These findings provide empirical support for a prenatal intervention that targets specific neural circuitries.

Breastfeeding Experiences of Mothers of Children with Down Syndrome.

Children with Down syndrome are less likely to be breastfed than typically developing children, and breastfeeding has a lower duration compared to recommendations of the World Health Organization. The aim of this study was to understand the breastfeeding experiences of mothers of children with Down syndrome, including their perceptions of the breastfeeding process and their specific practices. This is a qualitative study with 10 participants, mothers of children aged between 2 months and 9 years. Snowball sampling was used for participants' selection, and semi-structured interviews conducted in participants' households. Three categories emerged: "the breastfeeding experience," involving the process of breastfeeding, the breast milk, feelings, and difficulties of this practice; "experiences of health care," encompassing the support received by health professionals, dissatisfaction with health services, lack of support in breastfeeding, and discontent with health professional behavior; and "learning about Down syndrome," with search for information by parents and advice to health professionals. In this study, we found evidence that breastfeeding success relies very much on mothers' willingness and support of health professionals, namely, nurses. Findings from this study suggest that support of a multidisciplinary team is essential to the success of breastfeeding. Greater awareness is needed regarding the unique rewards and challenges of breastfeeding these infants, as well as how families cope with the ongoing challenges. Therefore, this research is relevant to understand the experiences of mothers of children with DS about breastfeeding, identifying the inhibiting factors, in order to create more appropriate strategies to intervene and implement practices that contribute to the support and promotion of breastfeeding. Results will also influence the education of health professionals, emphasizing the importance of multidisciplinary teams for a comprehensive care and contributing to increasing evidence available about this topic.

Estado nutricional y grado de actividad física en la población con síndrome de Down. Diseño y aplicación de un programa de Educación Nutricional (Programa NUTRIDOWN) / Nutritional status and physical activity level in the population with Down syndrome. Design and application of a nutrition education program (NUTRIDOWN)

Fundamentos: Las personas con síndrome de Down (SD) tienen mayor riesgo de presentar obesidad. Los objetivos del estudio fueron valorar el estado nutricional y grado de actividad física en el colectivo con SD, y aplicar un programa de educación nutricional (PEN) adaptado, para mejorar sus conocimientos sobre obesidad y alimentación saludable. Métodos: Se realizó un estudio descriptivo observacional sobre 16 personas con SD y discapacidad leve-moderada. Se midió el peso corporal, talla y perímetro abdominal. Se valoró la ingesta mediante un cuestionario de frecuencia de consumo de alimentos, el grado de adherencia a la dieta Mediterránea (DM) y el grado de actividad física. Además, se diseñó y aplicó un PEN. Resultados: La media de edad fue de 21,5 años. El 62,6% presentaba sobrepeso u obesidad y el 43,8% fueron sedentarios. Se observó una baja adherencia a la DM y un aumento de conocimientos mediante el programa. Conclusiones: Se observa un elevado porcentaje de sobrepeso y obesidad que podría ser debido al elevado sedentarismo y a la baja adherencia a la DM observados. Los PEN adaptados al colectivo mejoran sus conocimientos sobre alimentación saludable. Sin embargo, es necesario observar su efectividad a largo plazo (AU)

Background: People with Down syndrome (DS) have higher risk of suffering obesity. The aims of this study were to evaluate the nutritional status and the degree of physical activity in teenagers and adults with DS, as well as designing and applying a nutritional education programme (NEP) adapted in order to improve the knowledge about obesity and healthy dietary habits. Methods: A descriptive observational study was made to 16 people suffering from DS and minor-to-moderate intellectual disability. Body weight, height and waist circumference were measured. We assessed the dietary intake using a food frequency questionnaire, as well as the adherence to the mediterranean diet (MD) and the physical activity level. We designed and applied a NEP. Results: The mean age was 21.5 years. The 62.6 % were overweight or obese and the 43.8 % declared itself as sedentary. Low adherence to MD was observed and the programme increased their knowledge. Conclusions: We observed high rates of overweight and obesity that could be attributed to the high sedentary behaviour, the poor-quality diet and the low adherence to MD observed. NEP adapted to SD people can improve the knowledge about healthy eating. However, it is necessary to observe its long-term effectiveness (AU)

Differential effects of Epigallocatechin-3-gallate containing supplements on correcting skeletal defects in a Down syndrome mouse model.

SCOPE: Down syndrome (DS), caused by trisomy of human chromosome 21 (Hsa21), is characterized by a spectrum of phenotypes including skeletal abnormalities. The Ts65Dn DS mouse model exhibits similar skeletal phenotypes as humans with DS. DYRK1A, a kinase encoded on Hsa21, has been linked to deficiencies in bone homeostasis in DS mice and individuals with DS. Treatment with Epigallocatechin-3-gallate (EGCG), a known inhibitor of Dyrk1a, improves some skeletal abnormalities associated with DS in mice. EGCG supplements are widely available but the effectiveness of different EGCG-containing supplements has not been well studied. METHODS AND RESULTS: Six commercially available supplements containing EGCG were analyzed, and two of these supplements were compared with pure EGCG for their impact on skeletal deficits in a DS mouse model. The results demonstrate differential effects of commercial supplements on correcting skeletal abnormalities in Ts65Dn mice. Different EGCG-containing supplements display differences in degradation, polyphenol content, and effects on trisomic bone. CONCLUSION: This work suggests that the dose of EGCG and composition of EGCG-containing supplements may be important in correcting skeletal deficits associated with DS. Careful analyses of these parameters may lead to a better understanding of how to improve skeletal and other deficits that impair individuals with DS.

Fish oil improves gene targets of Down syndrome in C57BL and BALB/c mice.

We have considered a novel gene targeting approach for treating pathologies and conditions whose genetic bases are defined using diet and nutrition. One such condition is Down syndrome, which is linked to overexpression of RCAN1 on human chromosome 21 for some phenotypes. We hypothesize that a decrease in RCAN1 expression with dietary supplements in individuals with Down syndrome represents a potential treatment. Toward this, we used in vivo studies and bioinformatic analysis to identify potential healthy dietary RCAN1 expression modulators. We observed Rcan1 isoform 1 (Rcan1-1) protein reduction in mice pup hippocampus after a 4-week curcumin and fish oil supplementation, with only fish oil reduction being statistically significant. Focusing on fish oil, we observed a 17% Rcan1-1 messenger RNA (mRNA) and 19% Rcan1-1 protein reduction in BALB/c mice after 5 weeks of fish oil supplementation. Fish oil supplementation starting at conception and in a different mouse strain (C57BL) led to a 27% reduction in hippocampal Rcan1-1 mRNA and a 34% reduction in spleen Rcan1-1 mRNA at 6 weeks of age. Hippocampal protein results revealed a modest 11% reduction in RCAN1-1, suggesting translational compensation. Bioinformatic mining of human fish oil studies also revealed reduced RCAN1 mRNA expression, consistent with the above studies. These results suggest the potential use of fish oil in treating Down syndrome and support our strategy of using select healthy dietary agents to treat genetically defined pathologies, an approach that we believe is simple, healthy, and cost-effective.

Maternal choline supplementation differentially alters the basal forebrain cholinergic system of young-adult Ts65Dn and disomic mice.

Down syndrome (DS), trisomy 21, is a multifaceted condition marked by intellectual disability and early presentation of Alzheimer's disease (AD) neuropathological lesions including degeneration of the basal forebrain cholinergic neuron (BFCN) system. Although DS is diagnosable during gestation, there is no treatment option for expectant mothers or DS individuals. Using the Ts65Dn mouse model of DS that displays age-related degeneration of the BFCN system, we investigated the effects of maternal choline supplementation on the BFCN system in adult Ts65Dn mice and disomic (2N) littermates at 4.3-7.5 months of age. Ts65Dn dams were maintained on a choline-supplemented diet (5.1 g/kg choline chloride) or a control, unsupplemented diet with adequate amounts of choline (1 g/kg choline chloride) from conception until weaning of offspring; post weaning, offspring were fed the control diet. Mice were transcardially perfused with paraformaldehyde, and brains were sectioned and immunolabeled for choline acetyltransferase (ChAT) or p75-neurotrophin receptor (p75(NTR) ). BFCN number and size, the area of the regions, and the intensity of hippocampal labeling were determined. Ts65Dn-unsupplemented mice displayed region- and immunolabel-dependent increased BFCN number, larger areas, smaller BFCNs, and overall increased hippocampal ChAT intensity compared with 2N unsupplemented mice. These effects were partially normalized by maternal choline supplementation. Taken together, the results suggest a developmental imbalance in the Ts65Dn BFCN system. Early maternal-diet choline supplementation attenuates some of the genotype-dependent alterations in the BFCN system, suggesting this naturally occurring nutrient as a treatment option for pregnant mothers with knowledge that their offspring is trisomy 21.

Psoriasis first presenting around an enteral feeding tube in three pediatric patients: an important consideration for timely diagnosis and management.

Pediatric dermatologists may care for patients with percutaneous enteral feeding tubes. Although ostomy complications such as allergic contact and irritant dermatitis are common, psoriasis may be misdiagnosed. We report three novel cases of childhood psoriasis first presenting around an enteral feeding tube site. Localized psoriasis is an important clinical consideration in children with ostomy site eruptions to ensure timely diagnosis and effective management.

Bias and sensitivity analysis when estimating treatment effects from the cox model with omitted covariates.

Omission of relevant covariates can lead to bias when estimating treatment or exposure effects from survival data in both randomized controlled trials and observational studies. This paper presents a general approach to assessing bias when covariates are omitted from the Cox model. The proposed method is applicable to both randomized and non-randomized studies. We distinguish between the effects of three possible sources of bias: omission of a balanced covariate, data censoring and unmeasured confounding. Asymptotic formulae for determining the bias are derived from the large sample properties of the maximum likelihood estimator. A simulation study is used to demonstrate the validity of the bias formulae and to characterize the influence of the different sources of bias. It is shown that the bias converges to fixed limits as the effect of the omitted covariate increases, irrespective of the degree of confounding. The bias formulae are used as the basis for developing a new method of sensitivity analysis to assess the impact of omitted covariates on estimates of treatment or exposure effects. In simulation studies, the proposed method gave unbiased treatment estimates and confidence intervals with good coverage when the true sensitivity parameters were known. We describe application of the method to a randomized controlled trial and a non-randomized study.

Malnutrición extrema en una lactante de origen etíope con síndrome de Down / Extreme malnutrition in an infant of Ethiopian origin with Down’s syndrome

La observación de una lactante de origen etíope con síndrome de Down y malnutrición grave permite reflexionar sobre las condiciones sociales y sanitarias de Etiopía y las causas que han posibilitado que se llegue a esa situación extrema (AU)

Observation of an Ethiopian infant with Down’s syndrome with severe malnutrition, and reflection on the effect that the social and health conditions in Ethiopia had on the causes leading to this extreme situation (AU)

Síndrome de Down y enfermedad celíaca del adulto asociadas: estudio de casos / Down’s syndrome and celiac disease in the adult: description of a series of nine cases

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Características nutricionais das crianças e adolescentes portadoras de síndrome de Down da APAE de Caxias do Sul e São Marcos - RS / Nutritional characteristics of children and adolescents beares of Down syndrome from APAE Caxias do Sul and São Marcos - RS

Objetivos: Verificar as características nutricionais por meio do consumo alimentar e da avaliação antropométrica de crianças e adolescentes com Síndrome de Down na APAE de Caxias do Sul e São Marcos e identificar a prevalência de sobrepeso e obesidade nesta população. Método: Estudo transversal. A amostra foi composta por 18 indivíduos com Síndrome de Down, com idades entre 4 e 17 anos, da APAE de Caxias do Sul e São Marcos. Foi realizada avaliação antropométrica,onde foram verificados peso e estatura. Foi enviado para aos responsáveis desses indivíduos questionário socioeconômico e registro alimentar de três dias, para avaliação do consumo alimentar dos portadores de síndrome de Down...

Objective: To verify the nutritional characteristics through the alimentary consumption and of the anthropometric evaluation of children and adolescents bearers of Down syndrome at APAE Caxias do Sul and São Marcos also identify the prevalence of obesity and overweight in this population. Method: Transversal study. The sample was compounded by 18 individuals with Down syndrome, with ages between 4 and 17 years old from APAE of Caxias do Sul and São Marcos. It was made an anthropometric evaluation which was checked the stature and weight. It was sent to the responsible ones of these individuals a socioeconomic questionnaire and an alimentary register of three days to be evaluated the alimentary consumption of the bearers of Down syndrome...

Effect of zinc supplementation on thyroid hormone metabolism of adolescents with Down syndrome.

Studies have evidenced that zinc metabolism is altered in the presence of Down syndrome, and zinc seems to have a relationship with the metabolic alterations usually present in this syndrome. In this work, the effect of zinc supplementation on thyroid hormone metabolism was evaluated in adolescents with Down syndrome. A prospective study was carried out on 16 adolescents with Down syndrome (age: 10-19 years) who were randomized for treatment with 30 mg zinc daily for 4 weeks. Diet evaluation was accomplished y using a 3-day dietary record, and the analysis was performed by the NutWin program, version 1.5. Anthropometric measurements were performed for evaluation of body composition. The Zn-related nutritional status of the groups was evaluated by means of zinc concentration determinations in plasma and erythrocytes using the method of atomic absorption spectroscopy, and the thyroid hormone was obtained by radioimmunoassay. The diet of patients with Down syndrome, before and after the intervention presented reduced energy level and adequate zinc concentrations. Mean plasma zinc values were 59.2 +/- 13.2 and 71.0 +/- 21.9 microg/dL before and after the intervention, respectively. Erythrocyte concentrations of the mineral before supplementation, instead, were 51.5 microg/dL +/- 11.1 microg Zn/gHb, and at the end of the experiment, they were 42.9 +/- 8/5 microg Zn/gHb, with a significant statistical difference (p < 0.05). Serum concentrations of T(4) hormone before and after zinc supplementation were 1.26 +/- 0.20 and 1.54 +/- 0.63 pg/mL, respectively. Mean T(3) values before intervention were 2.47 +/- 037 pg/mL and, after supplementation, 2.25 +/- 0.67 pg/mL, without significant statistical difference (p > 0.05). Intervention with zinc showed to be effective in the stabilization of the concentrations of this mineral in plasma and erythrocytes, but had no influence on the metabolism of thyroid hormones.

Serum cholinesterases in Down syndrome children before and after nutritional supplementation.

INTRODUCTION: Down syndrome (DS) children have different degrees of developmental abnormalities associated with mental retardation. A cascade of pathological changes triggering alterations in cholinesterase-mediated functions seems to be the cause of neuronal and muscular dysfunctions, such as memory loss, disturbed cognitive skills, and language impairment in virtually all DS individuals, but there are currently no efficacious biomedical treatments for these central nervous system-associated impairments. The present study aimed to evaluate the effects of nutritional supplementation on cholinesterases in serum of DS children. METHODS: Activities of acetyl- and butyrylcholinesterase were analysed in the serum samples of 40 DS children, along with an equal number of age- and sex-matched controls under study. RESULTS: The activities of serum acetyl- and butyrylcholinesterase were found to be low in DS children before nutritional supplementation, compared to controls, and showed considerable improvement after six months of supplementation of zinc in combination with antioxidant vitamins and minerals. A significant improvement was also observed in cognitive skills and behavioural patterns after nutritional supplementation. CONCLUSION: The present pilot study suggests the significance of early intervention with nutritional supplementation in DS children to ameliorate the severity of this disorder.

Supplementation with antioxidants and folinic acid for children with Down's syndrome: randomised controlled trial.

OBJECTIVES: To assess whether supplementation with antioxidants, folinic acid, or both improves the psychomotor and language development of children with Down's syndrome. DESIGN: Randomised controlled trial with two by two factorial design. SETTING: Children living in the Midlands, Greater London, and the south west of England. PARTICIPANTS: 156 infants aged under 7 months with trisomy 21. INTERVENTION: Daily oral supplementation with antioxidants (selenium 10 mug, zinc 5 mg, vitamin A 0.9 mg, vitamin E 100 mg, and vitamin C 50 mg), folinic acid (0.1 mg), antioxidants and folinic acid combined, or placebo. MAIN OUTCOME MEASURES: Griffiths developmental quotient and an adapted MacArthur communicative development inventory 18 months after starting supplementation; biochemical markers in blood and urine at age 12 months. RESULTS: Children randomised to antioxidant supplements attained similar developmental outcomes to those without antioxidants (mean Griffiths developmental quotient 57.3 v 56.1; adjusted mean difference 1.2 points, 95% confidence interval -2.2 to 4.6). Comparison of children randomised to folinic acid supplements or no folinic acid also showed no significant differences in Griffiths developmental quotient (mean 57.6 v 55.9; adjusted mean difference 1.7, -1.7 to 5.1). No between group differences were seen in the mean numbers of words said or signed: for antioxidants versus none the ratio of means was 0.85 (95% confidence interval 0.6 to 1.2), and for folinic acid versus none it was 1.24 (0.87 to 1.77). No significant differences were found between any of the groups in the biochemical outcomes measured. Adjustment for potential confounders did not appreciably change the results. CONCLUSIONS: This study provides no evidence to support the use of antioxidant or folinic acid supplements in children with Down's syndrome. TRIAL REGISTRATION: Clinical trials NCT00378456.

Coenzyme Q10 (ubiquinol-10) supplementation improves oxidative imbalance in children with trisomy 21.

Endogenous coenzyme Q10 is an essential cofactor in the mitochondrial respiratory chain, a potent antioxidant, and a potential biomarker for systemic oxidative status. Evidence of oxidative stress was reported in individuals with trisomy 21. In this study, 14 children with trisomy 21 had significantly increased (P < 0.0001) plasma ubiquinone-10 (the oxidized component of coenzyme Q10) compared with 12 age- and sex-matched healthy children (historical controls). Also, the mean ratio of ubiquinol-10 (the biochemically reduced component):total coenzyme Q10 was significantly decreased (P < 0.0001). After 3 months of ubiquinol-10 supplementation (10 mg/kg/day) to 10 patients with trisomy 21, the mean ubiquinol-10:total coenzyme Q10 ratio increased significantly (P < 0.0001) above baseline values, and 80% of individual ratios were within normal range. No significant or unexpected adverse effects were reported by participants. To our knowledge, this is the first study to indicate that the pro-oxidant state in plasma of children with trisomy 21, as assessed by ubiquinol-10:total coenzyme Q10 ratio, may be normalized with ubiquinol-10 supplementation. Further studies are needed to determine whether correction of this oxidant imbalance improves clinical outcomes of children with trisomy 21.

Redox balance in patients with Down's syndrome before and after dietary supplementation with alpha-lipoic acid and L-cysteine.

The aim of the present study was to investigate the possible normalizing effect of antioxidants on certain parameters indicative of oxidative stress in Down's syndrome (DS). The study was performed in pediatric patients with DS with proven redox imbalance, who were advised to take a dietary supplementation composed of alpha-lipoic acid and L-cysteine for several treatment cycles (one treatment cycle = 30 days dietary supplementation plus 30 days wash-out). Serum thiol groups, serum total and septic reactive oxygen species (ROS) and total antioxidant status of serum were determined before and after dietary supplementation, using commercially available kits. In all the evaluable patients (n = 20), after 3.8 +/- 1.1 treatment cycles, thiol group serum concentrations and total antioxidant status of serum significantly increased (p < 0.0001 for both parameters) in comparison with basal values, while serum total and septic ROS significantly decreased (p < 0.0001 for both parameters). On the basis of these results it is impossible to demonstrate the clinical effects of the biochemical normalization obtained in patients with DS after supplying alpha-lipoic acid and L-cysteine. These data suggest that delaying the clinical expression of redox imbalance in patients with DS might be feasible by normalizing their redox balance.

Systematic review of the effect of therapeutic dietary supplements and drugs on cognitive function in subjects with Down syndrome.

The objective was to evaluate the effects of therapeutic dietary supplements and drugs on cognitive function in subjects with Down syndrome. The study design was a systematic review of randomized controlled trials of dietary supplements and/or drugs reporting any assessment of cognitive function in subjects with Down syndrome. Eleven trials were identified with 373 randomized participants. None of the trials reported cognitive enhancing effect in subjects with Down syndrome. Meta-analysis was not conducted due to the heterogeneous nature of the population, interventions and outcome measures used. Overall, the quality of the trials was poor with few subjects and generally inadequate allocation concealment of the treatments given. This comprehensive systematic review provides no positive evidence that any combination of drugs, vitamins and minerals enhance either cognitive function or psychomotor development in people with Down syndrome. However, because of the small number of subjects involved and the overall unsatisfactory quality of the trials, an effect cannot be excluded at this point. At present there is no justification for the use of such regimes outside the context of large well designed trials. Parents of children with Down syndrome should be actively discouraged from giving these 'miracle drugs' to their children.

Detection of apoptosis in peripheral blood cells of 31 subjects affected by Down syndrome before and after zinc therapy.

Thirty-one patients affected by Down syndrome (DS) were investigated to study the presence of apoptosis in peripheral blood cells in relation to the plasma levels of zinc. Twelve patients had undergone therapy with ZnSO4, while the remaining 19 were untreated. The presence of programmed cell death was evaluated by means of electron microscopy, in situ nick translation (NT), and agarose gel electrophoresis of DNA. These approaches evidenced the presence of apoptosis in peripheral blood cells of patients before therapy with ZnSO4, while after zinc supplementation there was a reduction in the number of apoptotic cells. These results suggest that the process of programmed cell death in peripheral blood cells of patients with Down syndrome is related to the plasma levels of zinc ion.