Time-scale synchronisation of oscillatory responses can lead to non-monotonous R-tipping.

Rate-induced tipping (R-tipping) describes the fact that, for multistable dynamic systems, an abrupt transition can take place not only because of the forcing magnitude, but also because of the forcing rate. In the present work, we demonstrate through the case study of a piecewise-linear oscillator (PLO), that increasing the rate of forcing can make the system tip in some cases but might also prevent it from tipping in others. This counterintuitive effect is further called non-monotonous R-tipping (NMRT) and has already been observed in recent studies. We show that, in the present case, the reason for NMRT is the peak synchronisation of oscillatory responses operating on different time scales. We further illustrate that NMRT can be observed even in the presence of additive white noise of intermediate amplitude. Finally, NMRT is also observed on a van-der-Pol oscillator with an unstable limit cycle, suggesting that this effect is not limited to systems with a discontinuous right-hand side such as the PLO. This insight might be highly valuable, as the current research on tipping elements is shifting from an equilibrium to a dynamic perspective while using models of increasing complexity, in which NMRT might be observed but hard to understand.

Efectividad del tratamiento con ondas de choque en la fascitis plantar / Effectiveness of shock wave treatment in plantar fasciitis

Introducción. Existe una gran heterogeneidad en los estudios que abordan la efectividad e indicación del tratamiento con ondas de choque (OCH) en la fascitis plantar (FP) respecto a otros tratamientos alternativos. Objetivos. Evaluar la efectividad del tratamiento con OCH en pacientes con FP mediante las evidencias científicas más actuales y evaluar la eficacia de este tratamiento en comparación con otros tipos de terapias también empleadas en el manejo de esta inflamación. Materiales y métodos. Se realizó una búsqueda bibliográfica en las bases de datos PubMed y PEDro con los términos clave "shock wave" y "plantar fasciitis AND shock wave". Se selecciona- ron artículos publicados en español e inglés entre los años 2015 y 2019. Resultados. Tras aplicar los criterios de inclusión y exclusión y luego de eliminar los duplica- dos, se seleccionaron 13 estudios que englobaban una muestra total de 1.220 individuos y comparaban las OCH frente a placebo, OCH con ejercicios, ultrasonoterapia, laserterapia de bajo nivel e infiltración de corticoides y toxina botulínica. Conclusión. Las OCH constituyen un método eficaz y seguro para tratar la FP, siendo más efectivo que la ultrasonoterapia y la infiltración de toxina botulínica, aunque existe controversia en el resto de comparaciones. Su uso se aconseja asociado a un programa de ejercicios; sin embargo, es necesario realizar más estudios sobre esta técnica.

Introduction. There is great heterogeneity in the studies that address the effectiveness and indication of shock wave therapy (SWT) in plantar fasciitis (PF) with respect to other alternative treatments. Objectives. To evaluate the effectiveness of OCH treatment in patients with PF using the most current scientific evidence and to assess the efficacy of this treatment in comparison with other types of therapies also used in the management of this inflammation. Materials and methods. A literature search was performed in the PubMed and PEDro databases with the key terms "shock wave" and "plantar fasciitis AND shock wave". Articles published in Spanish and English between 2015 and 2019 were selected. Results. After applying the inclusion and exclusion criteria and after eliminating duplicates, 13 studies were selected that encompassed a total sample of 1,220 individuals and compared OCH versus placebo, OCH with exercises, ultrasound therapy, low-level laser therapy, and corticosteroid and botulinum toxin infiltration. Conclusion. OCH is an effective and safe method to treat PF, being more effective than ultrasound therapy and botulinum toxin infiltration, although there is controversy in the rest of the comparisons. Its use is recommended in association with an exercise program; however, further studies on this technique are needed.

Relation among Oxygen Stoichiometry, Structure, and Co Valence and Spin State in Single-Layer La2-xAxCoO4±Î´ (A = Ca, Sr) Perovskites.

We have investigated the role of oxygen stoichiometry and structural properties in the modulation of Co valence and spin state in single-layer La2-xAxCoO4±Î´ (A = Sr, Ca; 0 ≤ x ≤ 1) perovskites as well as the interplay between their local structural properties and the magnetic and charge-ordering phenomena. We show the results of high angular resolution powder X-ray diffraction and Co K-edge X-ray absorption and emission spectroscopy experiments on polycrystalline and single-crystal samples. The different doping-induced changes in the Co valence and spin state by Ca (or Sr) substitution can be understood in terms of the evolving oxygen stoichiometry. For Ca doping, the interstitial oxygen excess around the La/Ca atoms in underdoped samples is rapidly lost upon increasing the Ca content. The creation of oxygen vacancies leads to the stabilization of a mixed-valence Co2.5+ independently of the Ca content. In contrast, Sr substitution leads to almost stoichiometric samples and a lower oxygen vacancy concentration, which allows higher mixed-valence states for Co up to Co2.9+. The Co mixed-valence state along the two series is fluctuating between two valence states, Co2.4+ as in La2CoO4.2 and Co2.9+ as in LaSrCoO3.91, that become periodically ordered for the charge-ordered phases around the half-doping. The X-ray emission derived spin states agree well with the Co fluctuating mixed-valence state derived from X-ray absorption spectroscopy on consideration of a distribution of high-spin Co2+ and low-spin Co3+. Furthermore, there is no quenching of the orbital contribution for the high-spin Co2+, as concluded from a comparison with macroscopic magnetization measurements. Doping holes are mainly located in the ab plane and have a strong oxygen 2p character. The major lattice distortions, which are different for Sr and Ca doping, occur along the c axis, where changes in the oxygen stoichiometry take place. Moreover, charge-order transitions are clearly shown from the anomalous increase of the c lattice parameter with an increase in the temperature above 500 K but there is no signature for a temperature-dependent spin-state transition.

Episodio de hipotonía e hiporrespuesta en el lactante / Hypotonic-hyporesponsive episode in early childhood

Se conoce como episodio de hipotonía-hiporrespuesta a un evento adverso de baja frecuencia de la vacunación infantil predominantemente del componente antitosferina. Es caracterizado por una pérdida súbita del tono muscular asociada a hiporreactividad a estímulos y a cambios en la coloración de la piel (palidez cutánea o cianosis). Debido a que es una entidad poco conocida, secundaria a mecanismos fisiopatológicos desconocidos y con diagnóstico por exclusión, adquiere una mayor importancia el conocimiento por el profesional sanitario de este evento, para elaborar un adecuado diagnóstico diferencial de episodios colapsiformes, evitar pruebas o medidas innecesarias y prevenir el miedo poblacional a las vacunas

Hypotonic-hyporesponsive episode is known as a rare vaccine adverse event in early childhood, mainly associated with antipertussis component. It is characterized by a sudden onset of reduced muscle tone, hyporesponsiveness and change of skin color (paleness or cyanosis). Because of being a little-known event with unknown pathophysiological mechanisms and a diagnosis by exclusion, its knowledge by the health professional takes on even greater importance for making an adequate differential diagnosis, avoiding unnecessary tests and preventing fear of vaccination in the society

Quantification of urinary derivatives of Phenylbutyric and Benzoic acids by LC-MS/MS as treatment compliance biomarkers in Urea Cycle disorders.

PURPOSE: Salts of phenylacetic acid (PAA) and phenylbutyric acid (PBA) have been used for nitrogen elimination as a treatment for hyperammonaemia caused by urea cycle disorders (UCD). A new analytical method for PBA measurement in urine which helps to evaluate the drug adherence has been implemented. METHODS: Urine specimens from UCD patients receiving PBA were analysed by tandem mass spectrometry to measure urine phenylacetylglutamine (PAGln). Some clinical and biochemical data for each patient were collected. RESULTS: Our study included 87 samples from 40 UCD patients. The PAGln levels did not correlate with height, weight or age. However, the PAGln values showed correlation with PBA dose (r = 0.383, P = 0.015). Plasma glutamine and ammonia levels presented a positive correlation (r = 0.537, P < 0.001). The stability for PAGln in urine was determined at different storage temperatures. CONCLUSIONS: We have developed a simple method for the determination of PAGln in urine, which acts as useful biomarker of effective drug delivery. PAGln in urine is stable at room temperature at least for 15 days, and for several months when frozen at -20 °C. This procedure is useful for the optimization and monitorization of the drug dose allowing the use of spot urine samples.

Structural, Magnetic, and Electronic Properties of CaBaCo4- xM xO7 (M = Fe, Zn).

The effect of substituting iron and zinc for cobalt in CaBaCo4O7 was investigated using neutron diffraction and X-ray absorption spectroscopy techniques. The orthorhombic distortion present in the parent compound CaBaCo4O7 decreases with increasing the content of either Fe or Zn. The samples CaBaCo3ZnO7 and CaBaCo4- xFe xO7 with x ≥ 1.5 are metrically hexagonal, but much better refinements in the neutron diffraction patterns are obtained using an orthorhombic unit cell. The two types of substitution have opposite effects on the structural and magnetic properties. Fe atoms preferentially occupy the sites at the triangular layer. Thus, the replacement of Co by Fe suppresses the ferrimagnetic ordering of the parent compound, and CaBaCo4- xFe xO7 (0.5 ≤ x ≤ 2) samples are antiferromagnetically ordered following a new propagation vector k = (1/3,0,0). However, the Zn atoms prefer occupying the Kagome layer, which is very detrimental for the long-range magnetic interactions giving rise to a magnetic glass-like behavior in the CaBaCo3ZnO7 sample. The oxidation states of iron and zinc are found to be 3+ and 2+, respectively, independently of the content, as confirmed by X-ray absorption spectroscopy. Therefore, the average Co oxidation state changes accordingly with the Fe3+ or Zn2+ doping. Also, X-ray absorption spectroscopy data confirm the different preferential occupation for both Fe and Zn cations. The combined information obtained by neutron diffraction and X-ray absorption spectroscopy indicates that cobalt atoms can be either in a fluctuating Co2+/Co3+ valence state or, alternatively, Co2+ and Co3+ ions being randomly distributed in the lattice. These results explain the occurrence of local disorder in the CoO4 tetrahedra obtained by EXAFS. An anomaly in the lattice parameters and an increase in the local disorder are observed only at the ferrimagnetic transition for CaBaCo4O7, revealing the occurrence of local magneto-elastic coupling.

Highly parallel direct RNA sequencing on an array of nanopores.

Sequencing the RNA in a biological sample can unlock a wealth of information, including the identity of bacteria and viruses, the nuances of alternative splicing or the transcriptional state of organisms. However, current methods have limitations due to short read lengths and reverse transcription or amplification biases. Here we demonstrate nanopore direct RNA-seq, a highly parallel, real-time, single-molecule method that circumvents reverse transcription or amplification steps. This method yields full-length, strand-specific RNA sequences and enables the direct detection of nucleotide analogs in RNA.

Genotype and phenotype characterization in a Spanish cohort with isovaleric acidemia.

Isovaleric acidemia (IVA) is a rare disorder of leucine metabolism. We carried out a multicenter study of IVA patients diagnosed by newborn screening (NBS) or symptoms clinics over a period of 28 years in Spain. Evaluated at diagnosis, data included age, detection method, levels of C5 and IVG, enzymatic studies, clinical presentation parameters and genotype in 16 patients. Follow-up data included C5 levels, intellectual quotient and correlation genotype-phenotype. IVA was detected by NBS in 8 patients (prevalence of 1/326 629). Except 1, all the 8 patients identified by NBS were asymptomatic at diagnosis and had isovalerylcarnitine (C5) levels of 1.6-6.4 µM and isovalerylglycine (IVG) levels <1100 mmol per mol creatinine; they remained asymptomatic with a natural protein intake ⩾1.5 g kg-1 per day. Symptomatic patients with chronic intermittent or acute neonatal IVA had C5 levels of 3.9-16.3 µM and IVG levels >3400 mmol per mol creatinine. The percentage of isovalerate incorporation in fibroblasts was 64-80% in patients detected by NBS and 4.9-13% in symptomatic patients. Cognitive function was within normal ranges in all patients but was negatively correlated with IVG at detection (-0.592; P<0.05). The genetic analysis revealed nine novel mutations. The clinical/biochemical phenotype correlated fairly well with the phenotype predicted by the mutations found. In conclusion, although blood C5 levels have traditionally been considered the prognostic marker of choice, urine IVG levels would appear to be a better predictor, as they correlated well with severity of mutations and were associated with a lower incorporation rate of IVA in fibroblasts and a less favorable clinical course.

Molecular epidemiology, genotype-phenotype correlation and BH4 responsiveness in Spanish patients with phenylketonuria.

Phenylketonuria (PKU), the most common inborn error of amino acid metabolism, is caused by mutations in the phenylalanine-4-hydroxylase (PAH) gene. This study aimed to assess the genotype-phenotype correlation in the PKU Spanish population and the usefulness in establishing genotype-based predictions of BH4 responsiveness in our population. It involved the molecular characterization of 411 Spanish PKU patients: mild hyperphenylalaninemia non-treated (mild HPA-NT) (34%), mild HPA (8.8%), mild-moderate (20.7%) and classic (36.5%) PKU. BH4 responsiveness was evaluated using a 6R-BH4 loading test. We assessed genotype-phenotype associations and genotype-BH4 responsiveness in our population according to literature and classification of the mutations. The mutational spectrum analysis showed 116 distinct mutations, most missense (70.7%) and located in the catalytic domain (62.9%). The most prevalent mutations were c.1066-11G>A (9.7%), p.Val388Met (6.6%) and p.Arg261Gln (6.3%). Three novel mutations (c.61-13del9, p.Ile283Val and p.Gly148Val) were reported. Although good genotype-phenotype correlation was observed, there was no exact correlation for some genotypes. Among the patients monitored for the 6R-BH4 loading test: 102 were responders (87, carried either one or two BH4-responsive alleles) and 194 non-responders (50, had two non-responsive mutations). More discrepancies were observed in non-responders. Our data reveal a great genetic heterogeneity in our population. Genotype is quite a good predictor of phenotype and BH4 responsiveness, which is relevant for patient management, treatment and follow-up.

Male Urinary Incontinence: Associated Risk Factors and Electromyography Biofeedback Results in Quality of Life.

The aim of the current study was to determine the demographic characteristics and risk factors associated with male urinary incontinence (UI) and to assess the effectiveness and the effect on the quality-of-life of a pelvic floor muscle training (PFMT) protocol with electromyography-biofeedback (EMG-BFB) with surface electrodes. A prospective, quasi-experimental before-and-after study with a sample of 61 men out of 372 patients referred to the Pelvic Floor Unit from October 2005 to June 2012 was performed. The protocol consisted of 20 sessions of EMG-BFB supervised by a physiotherapist twice a week. The session durations were 30 minutes (118 work/rest cycles of pelvic muscles). Work lasted 3 seconds and rest 7 seconds. Patients were given standards of conduct and questionnaires (International Consultation on Incontinence-Short Form and Incontinence Quality-of-Life Measure) at the beginning and at the end of the treatment. The average age was 64.85 ± 14.34 years; 44.3% (n = 27) had benign prostatic hypertrophy, 41.9% (n = 25) had prostate malignant neoplasm, 86.9% (n = 53) had undergone prostatectomy, 16.4% (n = 10) had undergone abdominal surgery. Abdominal surgery and radical prostatectomy were significantly associated with UI (p < .05). Stress urinary incontinence was the most common type of UI (86.67%), followed by mixed urinary incontinence (8.33%) and urge urinary incontinence (5%). A significant improvement (p < .05) in both International Consultation on Incontinence-Short Form and Incontinence Quality-of-Life Measure questionnaires was observed when making comparisons regarding the results before and after the EMG-BFB treatment protocol. These results support that male UI is significantly associated with urological and abdominal surgery (including radical prostatectomy) and that EMG-BFB for PFMT improves incontinence and quality of life (social embarrassment, limiting behavior, and psychosocial impact) in the three types of UI on an overall basis.

Epitaxial Stabilization of the Perovskite Phase in (Sr(1-x)Ba(x))MnO3 Thin Films.

A novel mechanism of ferroelectricity driven by off-centering magnetic Mn(4+) ions was proposed in (Sr1-xBax)MnO3, in its ideal perovskite phase, which yields enormous expectations in the search for strong magnetoelectric materials. Still, the desired perovskite phase has never been stabilized in thin films due to its extremely metastable character. Here, we report on a thorough study of the perovskite phase stabilization of (Sr1-xBax)MnO3 thin films, 0.2 ≤ x ≤ 0.5, grown by pulsed laser deposition onto (001)-oriented perovskite substrates. X-ray diffraction measurements and scanning transmission electron microscopy reveal that, under appropriate deposition conditions, the perovskite phase is fully stabilized over the nonferroelectric hexagonal phase, despite the latter being increasingly favored on increasing Ba-content. Moreover, we have managed to grow epitaxial coherent cube-on-cube (Sr1-xBax)MnO3 films upon strains ranging from 0% to 4%. Our results become a milestone in further studying perovskite (Sr1-xBax)MnO3 thin films and pave the way for tailoring ferroic and magnetoelectric properties either by strain engineering or Ba-doping.

Strain-induced coupling of electrical polarization and structural defects in SrMnO3 films.

Local perturbations in complex oxides, such as domain walls, strain and defects, are of interest because they can modify the conduction or the dielectric and magnetic response, and can even promote phase transitions. Here, we show that the interaction between different types of local perturbations in oxide thin films is an additional source of functionality. Taking SrMnO3 as a model system, we use nonlinear optics to verify the theoretical prediction that strain induces a polar phase, and apply density functional theory to show that strain simultaneously increases the concentration of oxygen vacancies. These vacancies couple to the polar domain walls, where they establish an electrostatic barrier to electron migration. The result is a state with locally structured room-temperature conductivity consisting of conducting nanosized polar domains encased by insulating domain boundaries, which we resolve using scanning probe microscopy. Our 'nanocapacitor' domains can be individually charged, suggesting stable capacitance nanobits with a potential for information storage technology.

6R-tetrahydrobiopterin treated PKU patients below 4 years of age: Physical outcomes, nutrition and genotype.

BACKGROUND AND AIMS: Phenylalanine-restricted diets have proven effective in treating phenylketonuria. However, such diets have occasionally been reported to hinder normal development. Our study aimed to assess whether treating 0-4-year-old phenylketonuric patients with 6R-tetrahydrobiopterin might prevent growth retardation later in life. METHODS: We conducted a longitudinal retrospective study which examined anthropometric characteristics of phenylketonuric patients on 6R-tetrahydrobiopterin therapy (22 subjects), and compared them with a group of phenylketonuric patients on protein-restricted diets (44 subjects). Nutritional issues were also considered. We further explored possible relationships between mutations in the PAH gene, BH4 responsiveness and growth outcome. RESULTS: No significant growth improvements were observed in either the group on 6R-tetrahydrobiopterin treatment (height Z-score: initial= -0.57 ± 1.54; final=-0.52 ± 1.29; BMI Z-score: initial=0.17 ± 1.05; final=0.18 ± 1.00) or the diet-only group (height Z-score: initial=-0.92 ± 0.96; final= -0.78 ± 1.08; BMI Z-score: initial=0.17 ± 0.97; final=-0.07 ± 1.03) over the 1-year observation period. Furthermore, we found no significant differences (p>0.05) between the two groups at any of the time points considered (0, 6 and 12 months). Patients on 6R-tetrahydrobiopterin increased their phenylalanine intake (from 49.1 [25.6-60.3] to 56.5 [39.8-68.3] mgkg(-1)day(-1)) and natural protein intake (from 1.0 [0.8-1.7] to 1.5 [1.0-1.8] g kg(-1)day(-1)), and some patients managed to adopt normal diets. Higher phenylalanine and natural protein intakes were positively correlated with better physical outcomes in the diet-only group (p<0.05). No correlation was found between patient genotype and physical outcomes, results being similar regardless of the nutritional approach used. We did not detect any side effects due to 6R-tetrahydrobiopterin administration. CONCLUSIONS: Our study indicates that treating 0-4-year-old phenylketonuric patients with 6R-tetrahydrobiopterin is safe. However, poor developmental outcomes were observed, despite increasing the intake of natural proteins. Genotype could be a valid predictor of tetrahydrobiopterin-responsiveness, since patients who carried the same genotype responded similarly to the 6R-tetrahydrobiopterin loading test. On the other hand, harbouring 6R-tetrahydrobiopterin responsive genotypes did not predispose patients to better physical outcomes.

Recombinant human leptin treatment in genetic lipodystrophic syndromes: the long-term Spanish experience.

Lipodystrophies are a group of diseases mainly characterized by a loss of adipose tissue and frequently associated with insulin resistance, hypertriglyceridemia, and hepatic steatosis. In uncommon lipodystrophies, these complications frequently are difficult to control with conventional therapeutic approaches. This retrospective study addressed the effectiveness of recombinant methionyl leptin (metreleptin) for improving glucose metabolism, lipid profile, and hepatic steatosis in patients with genetic lipodystrophic syndromes. We studied nine patients (five females and four males) with genetic lipodystrophies [seven with Berardinelli-Seip syndrome, one with atypical progeroid syndrome, and one with type 2 familial partial lipodystrophy (FPLD)]. Six patients were children under age 9 years, and all patients had baseline triglycerides levels >2.26 mmol/L and hepatic steatosis; six had poorly controlled diabetes mellitus. Metreleptin was self-administered subcutaneously daily at a final dose that ranged between 0.05 and 0.24 mg/(kg day) [median: 0.08 mg/(kg day)] according to the body weight. The duration of treatment ranged from 9 months to 5 years, 9 months (median: 3 years). Plasma glucose, hemoglobin A1c (Hb A1c), lipid profile, plasma insulin and leptin, and hepatic enzymes were evaluated at baseline and at least every 6 months. Except for the patient with FPLD, metreleptin replacement significantly improved metabolic control (Hb A1c: from 10.4 to 7.1 %, p < 0.05). Plasma triglycerides were reduced 76 % on average, and hepatic enzymes decreased more than 65 %. This study extends knowledge about metreleptin replacement in genetic lipodystrophies, bearing out its effectiveness for long periods of time.

Prebiotic effect during the first year of life in healthy infants fed formula containing GOS as the only prebiotic: a multicentre, randomised, double-blind and placebo-controlled trial.

PURPOSE: Currently, there is no consensus concerning the possible beneficial colonic and systemic effects of prebiotic-containing infant formula. This study assesses whether the feeding of a galactooligosaccharides (GOS)-containing infant formula (0.44 g/dl of GOS) and the subsequent feeding of a GOS-containing follow-on formula (0.50 g/dl of GOS) have a prebiotic effect on intestinal microbiota that helps to decrease infections and allergy manifestations in healthy infants during the first year of life. METHODS: A multicentre, randomised, double-blind and placebo-controlled trial was carried out on 365 healthy term infants enrolled before 8 weeks of age and randomly assigned to a formula with or without GOS, until 12 months of age. The incidence of infections and allergy manifestations, the antibiotics prescribed and faecal characteristics were recorded up to 12 months of age, while faecal samples were collected up to 4 months for the measurement of secretory immunoglobulin A, short-chain fatty acids and microbiota. RESULTS: A prebiotic effect on the faecal analysis was observed at 4 months of life. The GOS group showed a lower faecal pH (P = 0.019), a lower decreasing trend in secretory immunoglobulin A (P = 0.078), lower butyric acid concentration (P = 0.040) and an increase in Bifidobacterium counts (P = 0.010). Changes in faecal characteristics involved greater frequency (P < 0.001) and softer consistency (P < 0.05). The incidence of infections or allergic manifestations during the first year of life was similar in both groups, with no statistical differences (P > 0.05). CONCLUSIONS: The feeding of GOS-containing infant formula produced a definite prebiotic effect consisting of changes in faecal composition and microbiota, and in faecal consistency and the frequency of defaecation. No changes in the incidence of infection or allergic manifestation during the first year of life were observed.

Anthropometric characteristics and nutrition in a cohort of PAH-deficient patients.

BACKGROUND & AIMS: Treating phenylketonuria based upon strict vegetarian diets has occasionally been found to hamper physical development, some patients presenting with growth retardation and malnutrition. In addition, some researchers have reported an association between higher protein intakes and attaining better developmental outcomes, although it remains unclear which protein fraction (natural or synthetic) has the greatest influence on growth. The present study aimed to evaluate anthropometric characteristics and nutrition in a cohort of patients with phenylketonuria and mild-hyperphenylalaninaemia from birth to adulthood. METHODS: We conducted a retrospective longitudinal study comparing anthropometric characteristics (weight, height, body mass index, and growth rate) in our patients and healthy subjects, with the measurements expressed as z-scores. Nutritional issues were also considered. Data were collected every 6 months from birth to 18 years of age. RESULTS: Growth impairment was observed in phenylketonuric patients. Specifically, there were two well-differentiated periods throughout which height fell well below z-score = 0: from birth to two years of age, and on reaching adulthood. We also found height and weight to be positively correlated with phenylalanine intake. No growth retardation was seen in the patients with mild-hyperphenylalaninaemia. CONCLUSIONS: Phenylketonuric patients showed growth impairment in the early stages, with higher phenylalanine intakes being associated with attaining better developmental outcomes in this period. Therefore, prescribing very stringent diets in the early years might predispose phenylketonuric patients to retarded growth later in life, with growth outcomes in adulthood being well below the 50th percentile for healthy subjects.

Tetrahydrobiopterin therapy vs phenylalanine-restricted diet: impact on growth in PKU.

BACKGROUND: Treatment of phenylketonuria based upon strict vegetarian diets, with very low phenylalanine intake and supplemented by phenylalanine-free formula, has proven to be effective in preventing the development of long-term neurological sequelae due to phenylalanine accumulation. On the other hand, such diets have occasionally been reported to hinder normal development, some individuals presenting with growth retardation. Tetrahydrobiopterin therapy has opened up new treatment options for a significant proportion of phenylketonuric patients, enabling them to eat normal diets and be freed from the need to take synthetic supplements. However, little is known about how this therapy affects their physical development. METHODS: We conducted a retrospective longitudinal study examining anthropometric characteristics (height, weight, body mass index and growth speed Z-scores) in a cohort of phenylketonuric patients on tetrahydrobiopterin therapy (38 subjects) comparing their characteristics with those of a group of phenylketonuric patients on phenylalanine-restricted diets (76 subjects). Nutritional issues were also considered, to further explore the possibility of higher natural protein intake being associated with better physical development. Data were collected every six months over two different periods of time (two or five years). RESULTS: No improvement was observed in the aforementioned anthropometric variables in the cohort on tetrahydrobiopterin therapy, from prior to starting treatment to when they had been taking the drug for two or five years. Rather, in almost all cases there was a fall in the mean Z-score for the variables during these periods, although the changes were not significant in any case. Further, we found no statistically differences between the two groups at any considered time point. Growth impairment was also noted in the phenylketonuric patients on low-phenylalanine diets. Individuals on tetrahydrobiopterin therapy increased their natural protein intake and, in some instances, this treatment enabled individuals to eat normal diets, with protein intake meeting RDAs. No association was found, however, between higher protein intake and growth. CONCLUSION: Our study identified growth impairment in patients with phenylketonuria on tetrahydrobiopterin, despite higher intakes of natural proteins. In fact, individuals undergoing long-term tetrahydrobiopterin treatment seemed to achieve similar developmental outcomes to those attained by individuals on more restricted diets.

Incommensurate sinusoidal oxygen modulations in layered manganites La(1-x)Sr(1+x)MnO4 (x≥0.5).

We have studied the incommensurate-ordered phase in overdoped La0.4Sr1.6MnO4 by resonant x-ray diffraction at the Mn K edge. Weak resonant superlattice (h±0.2 h±0.2 0) and (h±0.4 h±0.4 0) reflections of the tetragonal structure were found below ~240 K. The energy, azimuth angle, and polarization dependencies of the resonant scattering have revealed sinusoidal modulations of the oxygen motions that are transverse and longitudinal to the tetragonal [110] direction. This result discards (Mn(3+),Mn(4+))-like stripe-type order but point to a charge-density-modulation picture.

Structural distortion, charge modulation and local anisotropies in magnetite below the Verwey transition using resonant X-ray scattering.

The pattern of charge modulations and local anisotropies below the Verwey transition has been determined and quantified in high-quality Fe(3)O(4) single crystals and thin films grown on MgO by using resonant X-ray scattering at the Fe K-edge. The energy, polarization and azimuthal angle dependencies of an extensive set of reflections with potential sensitivity to charge or local anisotropy orderings have been analyzed to explore their origins. A charge disproportion on octahedral B sites of 0.20 ± 0.05 e(-) with [0 0 1] and [1 1 0] cubic periodicities has been confirmed, while no significant charge disproportion has been obtained with [0 0 1/2] cubic periodicity. Additional charge modulations in the monoclinic a-b plane are also present. In addition, the occurrence of new forbidden (1, 1, 0) and (0, 0, 2n + 1/2) cubic reflections that arise from the anisotropy of the local structure around different tetrahedral and octahedral Fe atoms is shown. This complex pattern of weak charge modulations and local anisotropies is fully compatible with the low-temperature crystal structure refined in the non-polar C2/c space group and disproves any bimodal charge disproportion of the octahedral Fe atoms.