Circadian and ultradian cardiovascular rhythmicity in obese children.

UNLABELLED Altered circadian and ultradian blood pressure (BP) and heart rate (HR) rhythmicity have been described in diseases with increased cardiovascular risk. We analyzed cardiovascular rhythmicity in obese children. BP and HR rhythmicity was assessed with Fourier analysis from 24-h ambulatory BP measurements in 75 obese children and compared with an age- and gender-matched, lean healthy reference group of 150 subjects. Multivariate regression analysis was applied to identify significant independent factors explaining variability of rhythmicity. Prevalence of 24- and 6-h BP rhythmicity in the obese group was lower (p = 0.03 and p = 0.02), whereas the prevalence of HR rhythmicity was comparable in both groups. Excluding hypertensive participants, the results remained similar. Twenty-four-hour BP and HR acrophase were delayed in obese children (p = 0.004, p < 0.0001), 24-h BP amplitude did not differ (p = 0.07), and 24-h HR amplitude was blunted (p = < 0.0001). BP Mesor in the obese group was higher (p = 0.02); HR Mesor did not differ (p = 0.1). Multivariate regression analysis failed to identify a single anthropometric or blood pressure parameter explaining the variability of BP and HR rhythmicity. CONCLUSION Prevalence and parameters of circadian and ultradian BP and HR rhythmicity in obese children are altered compared to a healthy reference group, independent of preexisting hypertension. WHAT IS KNOWN • Altered cardiovascular rhythmicity has been described in children with different diseases such as primary hypertension or chronic renal failure. What is New: • This study reveals altered cardiovascular rhythmicity in obese children compared to an age and gender-matched healthy reference group independent from preexisting hypertension

Clinically practical pharmacometrics computer model to evaluate and personalize pharmacotherapy in pediatric rare diseases: application to Graves' disease

ObjectivesGraves' disease (GD) with onset in childhood or adolescence is a rare disease (ORPHA:525731). Current pharmacotherapeutic approaches use antithyroid drugs, such as carbimazole, as monotherapy or in combination with thyroxine hormone substitutes, such as levothyroxine, as block-and-replace therapy to normalize thyroid function and improve patients' quality of life. However, in the context of fluctuating disease activity, especially during puberty, a considerable proportion of pediatric patients with GD is suffering from thyroid hormone concentrations outside the therapeutic reference ranges. Our main goal was to develop a clinically practical pharmacometrics computer model that characterizes and predicts individual disease activity in children with various severity of GD under pharmacotherapy.MethodsRetrospectively collected clinical data from children and adolescents with GD under up to two years of treatment at four different pediatric hospitals in Switzerland were analyzed. Development of the pharmacometrics computer model is based on the non-linear mixed effects approach accounting for inter-individual variability and incorporating individual patient characteristics. Disease severity groups were defined based on free thyroxine (FT4) measurements at diagnosis.ResultsData from 44 children with GD (75% female, median age 11 years, 62% receiving monotherapy) were analyzed. FT4 measurements were collected in 13, 15, and 16 pediatric patients with mild, moderate, or severe GD, with a median FT4 at diagnosis of 59.9 pmol/l (IQR 48.4, 76.8), and a total of 494 FT4 measurements during a median follow-up of 1.89 years (IQR 1.69, 1.97). We observed no notable difference between severity groups in terms of patient characteristics, daily carbimazole starting doses, and patient years. The final pharmacometrics computer model was developed based on FT4 measurements and on carbimazole or on carbimazole and levothyroxine doses involving two clinically relevant covariate effects: age at diagnosis and disease severity.DiscussionWe present a tailored pharmacometrics computer model that is able to describe individual FT4 dynamics under both, carbimazole monotherapy and carbimazole/levothyroxine block-and-replace therapy accounting for inter-individual disease progression and treatment response in children and adolescents with GD. Such clinically practical and predictive computer model has the potential to facilitate and enhance personalized pharmacotherapy in pediatric GD, reducing over- and underdosing and avoiding negative short- and long-term consequences. Prospective randomized validation trials are warranted to further validate and fine-tune computer-supported personalized dosing in pediatric GD and other rare pediatric diseases

Engineering Zymomonas mobilis for the production of xylonic acid from sugarcane bagasse hydrolysate

Sugarcane bagasse is an agricultural residue rich in xylose, which may be used as a feedstock for the production of high-value-added chemicals, such as xylonic acid, an organic acid listed as one of the top 30 value-added chemicals on a NREL report. Here, Zymomonas mobilis was engineered for the first time to produce xylonic acid from sugarcane bagasse hydrolysate. Seven coding genes for xylose dehydrogenase (XDH) were tested. The expression of XDH gene from Paraburkholderia xenovorans allowed the highest production of xylonic acid (26.17 ± 0.58 g L−1) from 50 g L−1 xylose in shake flasks, with a productivity of 1.85 ± 0.06 g L−1 h −1 and a yield of 1.04 ± 0.04 gAX/gX. Deletion of the xylose reductase gene further increased the production of xylonic acid to 56.44 ± 1.93 g L−1 from 54.27 ± 0.26 g L−1 xylose in a bioreactor. Strain performance was also evaluated in sugarcane bagasse hydrolysate as a cheap feedstock, which resulted in the production of 11.13 g L−1 xylonic acid from 10 g L−1 xylose. The results show that Z. mobilis may be regarded as a potential platform for the production of organic acids from cheap lignocellulosic biomass in the context of biorefineries

El mundo rural de Mágina. Una aproximación ecocrítica a El viento de la Luna de Antonio Muñoz Molina

In El viento de la Luna (The Wind of the Moon) Antonio Muñoz Molina returns to the imaginary world of Mágina, a place where Nature plays a determinant role. Our ecocritic lecture is focussing on the relation between mankind and environment.En El viento de la Luna Antonio Muñoz Molina regresa al mundo imaginario de Mágina, espacio en el que la Naturaleza desempeña un papel determinante. Nuestra lectura ecocrítica sitúa en un primer plano la relación entre el hombre y el medio ambiente

Impact of Type 1 Diabetes Mellitus on Bone Health in Children

This paper gives an overview of the impact of type 1 diabetes on bone health in children and adolescents. Firstly, we analyse studies using dual X-ray absorptiometry to assess bone mineral content and bone mineral density. Then, we discuss modern, non-invasive techniques including peripheral quantitative computer tomography (pQCT) and high-resolution pQCT for the detailed assessment of bone health aspects including bone mass, bone geometry, bone microarchitecture, and bone strength. Thereafter, we explore some of the mechanisms that are responsible for diabetic bone disease in children, like low bone turnover and high sclerostin levels. Finally, we summarize some of the evidence for the importance of microvascular disease in the pathophysiology of diabetic bone diseas

Autosomal-Recessive Mutations in MESD Cause Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) comprises a genetically heterogeneous group of skeletal fragility diseases. Here, we report on five independent families with a progressively deforming type of OI, in whom we identified four homozygous truncation or frameshift mutations in MESD. Affected individuals had recurrent fractures and at least one had oligodontia. MESD encodes an endoplasmic reticulum (ER) chaperone protein for the canonical Wingless-related integration site (WNT) signaling receptors LRP5 and LRP6. Because complete absence of MESD causes embryonic lethality in mice, we hypothesized that the OI-associated mutations are hypomorphic alleles since these mutations occur downstream of the chaperone activity domain but upstream of ER-retention domain. This would be consistent with the clinical phenotypes of skeletal fragility and oligodontia in persons deficient for LRP5 and LRP6, respectively. When we expressed wild-type (WT) and mutant MESD in HEK293T cells, we detected WT MESD in cell lysate but not in conditioned medium, whereas the converse was true for mutant MESD. We observed that both WT and mutant MESD retained the ability to chaperone LRP5. Thus, OI-associated MESD mutations produce hypomorphic alleles whose failure to remain within the ER significantly reduces but does not completely eliminate LRP5 and LRP6 trafficking. Since these individuals have no eye abnormalities (which occur in individuals completely lacking LRP5) and have neither limb nor brain patterning defects (both of which occur in mice completely lacking LRP6), we infer that bone mass accrual and dental patterning are more sensitive to reduced canonical WNT signaling than are other developmental processes. Biologic agents that can increase LRP5 and LRP6-mediated WNT signaling could benefit individuals with MESD-associated OI