Clinical practice guidelines for the diagnosis and management of Charcot-Marie-Tooth disease.

INTRODUCTION: Charcot-Marie-Tooth disease (CMT) is classified according to neurophysiological and histological findings, the inheritance pattern, and the underlying genetic defect. The objective of these guidelines is to offer recommendations for the diagnosis, prognosis, follow-up, and treatment of this disease in Spain. MATERIAL AND METHODS: These consensus guidelines were developed through collaboration by a multidisciplinary panel encompassing a broad group of experts on the subject, including neurologists, paediatric neurologists, geneticists, physiatrists, and orthopaedic surgeons. RECOMMENDATIONS: The diagnosis of CMT is clinical, with patients usually presenting a common or classical phenotype. Clinical assessment should be followed by an appropriate neurophysiological study; specific recommendations are established for the parameters that should be included. Genetic diagnosis should be approached sequentially; once PMP22 duplication has been ruled out, if appropriate, a next-generation sequencing study should be considered, taking into account the limitations of the available techniques. To date, no pharmacological disease-modifying treatment is available, but symptomatic management, guided by a multidiciplinary team, is important, as is proper rehabilitation and orthopaedic management. The latter should be initiated early to identify and improve the patient's functional deficits, and should include individualised exercise guidelines, orthotic adaptation, and assessment of conservative surgeries such as tendon transfer. The follow-up of patients with CMT is exclusively clinical, and ancillary testing is not necessary in routine clinical practice.

Epigenetic effects of folate and related B vitamins on brain health throughout life: Scientific substantiation and translation of the evidence for health improvement strategies.

Suboptimal status of folate and/or interrelated B vitamins (B12 , B6 and riboflavin) can perturb one-carbon metabolism and adversely affect brain development in early life and brain function in later life. Human studies show that maternal folate status during pregnancy is associated with cognitive development in the child, whilst optimal B vitamin status may help to prevent cognitive dysfunction in later life. The biological mechanisms explaining these relationships are not clear but may involve folate-related DNA methylation of epigenetically controlled genes related to brain development and function. A better understanding of the mechanisms linking these B vitamins and the epigenome with brain health at critical stages of the lifecycle is necessary to support evidence-based health improvement strategies. The EpiBrain project, a transnational collaboration involving partners in the United Kingdom, Canada and Spain, is investigating the nutrition-epigenome-brain relationship, particularly focussing on folate-related epigenetic effects in relation to brain health outcomes. We are conducting new epigenetics analysis on bio-banked samples from existing well-characterised cohorts and randomised trials conducted in pregnancy and later life. Dietary, nutrient biomarker and epigenetic data will be linked with brain outcomes in children and older adults. In addition, we will investigate the nutrition-epigenome-brain relationship in B vitamin intervention trial participants using magnetoencephalography, a state-of-the-art neuroimaging modality to assess neuronal functioning. The project outcomes will provide an improved understanding of the role of folate and related B vitamins in brain health, and the epigenetic mechanisms involved. The results are expected to provide scientific substantiation to support nutritional strategies for better brain health across the lifecycle.

Structural, vibrational and electronic properties of α'-Ga2S3 under compression.

We report a joint experimental and theoretical study of the low-pressure phase of α'-Ga2S3 under compression. Theoretical ab initio calculations have been compared to X-ray diffraction and Raman scattering measurements under high pressure carried out up to 17.5 and 16.1 GPa, respectively. In addition, we report Raman scattering measurements of α'-Ga2S3 at high temperature that have allowed us to study its anharmonic properties. To understand better the compression of this compound, we have evaluated the topological properties of the electron density, the electron localization function, and the electronic properties as a function of pressure. As a result, we shed light on the role of the Ga-S bonds, the van der Waals interactions inside the channels of the crystalline structure, and the single and double lone electron pairs of the sulphur atoms in the anisotropic compression of α'-Ga2S3. We found that the structural channels are responsible for the anisotropic properties of α'-Ga2S3 and the A'(6) phonon, known as the breathing mode and associated with these channels, exhibits the highest anharmonic behaviour. Finally, we report calculations of the electronic band structure of α'-Ga2S3 at different pressures and find a nonlinear pressure behaviour of the direct band gap and a pressure-induced direct-to-indirect band gap crossover that is similar to the behaviour previously reported in other ordered-vacancy compounds, including ß-Ga2Se3. The importance of the single and, more specially, the double lone electron pairs of sulphur in the pressure dependence of the topmost valence band of α'-Ga2S3 is stressed.

Differential levels of Neurofilament Light protein in cerebrospinal fluid in patients with a wide range of neurodegenerative disorders.

Cerebrospinal fluid (CSF) biomarkers are useful in the diagnosis and the prediction of progression of several neurodegenerative diseases. Among them, CSF neurofilament light (NfL) protein has particular interest, as its levels reflect neuroaxonal degeneration, a common feature in various neurodegenerative diseases. In the present study, we analyzed NfL levels in the CSF of 535 participants of the SPIN (Sant Pau Initiative on Neurodegeneration) cohort including cognitively normal participants, patients with Alzheimer disease (AD), Down syndrome (DS), frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), dementia with Lewy bodies (DLB), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). We evaluated the differences in CSF NfL accross groups and its association with other CSF biomarkers and with cognitive scales. All neurogenerative diseases showed increased levels of CSF NfL, with the highest levels in patients with ALS, FTD, CBS and PSP. Furthermore, we found an association of CSF NfL levels with cognitive impairment in patients within the AD and FTD spectrum and with AD pathology in DLB and DS patients. These results have implications for the use of NfL as a marker in neurodegenerative diseases.

High-pressure characterization of multifunctional CrVO4.

The structural stability and physical properties of CrVO4 under compression were studied by x-ray diffraction, Raman spectroscopy, optical absorption, resistivity measurements, and ab initio calculations up to 10 GPa. High-pressure x-ray diffraction and Raman measurements show that CrVO4 undergoes a phase transition from the ambient pressure orthorhombic CrVO4-type structure (Cmcm space group, phase III) to the high-pressure monoclinic CrVO4-V phase, which is proposed to be isomorphic to the wolframite structure. Such a phase transition (CrVO4-type → wolframite), driven by pressure, also was previously observed in indium vanadate. The crystal structure of both phases and the pressure dependence in unit-cell parameters, Raman-active modes, resistivity, and electronic band gap, are reported. Vanadium atoms are sixth-fold coordinated in the wolframite phase, which is related to the collapse in the volume at the phase transition. Besides, we also observed drastic changes in the phonon spectrum, a drop of the band-gap, and a sharp decrease of resistivity. All the observed phenomena are explained with the help of first-principles calculations.

Mental performance in 8-year-old children fed reduced protein content formula during the 1st year of life: safety analysis of a randomised clinical trial.

In humans, maximum brain development occurs between the third trimester of gestation and 2 years of life. Nutrition during these critical windows of rapid brain development might be essential for later cognitive functioning and behaviour. In the last few years, trends on protein recommendations during infancy and childhood have tended to be lower than that in the past. It remains to be demonstrated that lower protein intakes among healthy infants, a part of being able to reduce obesity risk, is safe in terms of mental performance achievement. Secondary analyses of the EU CHOP, a clinical trial in which infants from five European countries were randomised to be fed a higher or a lower protein content formula during the 1st year of life. Children were assessed at the age of 8 years with a neuropsychological battery of tests that included assessments of memory (visual and verbal), attention (visual, selective, focused and sustained), visual-perceptual integration, processing speed, visual-motor coordination, verbal fluency and comprehension, impulsivity/inhibition, flexibility/shifting, working memory, reasoning, visual-spatial skills and decision making. Internalising, externalising and total behaviour problems were assessed using the Child Behaviour Checklist 4-18. Adjusted analyses considering factors that could influence neurodevelopment, such as parental education level, maternal smoking, child's gestational age at birth and head circumference, showed no differences between feeding groups in any of the assessed neuropsychological domains and behaviour. In summary, herewith we report on the safety of lower protein content in infant formulae (closer to the content of human milk) according to long-term mental performance.

Phase stability and electronic structure of iridium metal at the megabar range.

The 5d transition metals have attracted specific interest for high-pressure studies due to their extraordinary stability and intriguing electronic properties. In particular, iridium metal has been proposed to exhibit a recently discovered pressure-induced electronic transition, the so-called core-level crossing transition at the lowest pressure among all the 5d transition metals. Here, we report an experimental structural characterization of iridium by x-ray probes sensitive to both long- and short-range order in matter. Synchrotron-based powder x-ray diffraction results highlight a large stability range (up to 1.4 Mbar) of the low-pressure phase. The compressibility behaviour was characterized by an accurate determination of the pressure-volume equation of state, with a bulk modulus of 339(3) GPa and its derivative of 5.3(1). X-ray absorption spectroscopy, which probes the local structure and the empty density of electronic states above the Fermi level, was also utilized. The remarkable agreement observed between experimental and calculated spectra validates the reliability of theoretical predictions of the pressure dependence of the electronic structure of iridium in the studied interval of compressions.

Stability and nature of the volume collapse of ε-Fe2O3 under extreme conditions.

Iron oxides are among the major constituents of the deep Earth's interior. Among them, the epsilon phase of Fe2O3 is one of the less studied polymorphs and there is a lack of information about its structural, electronic and magnetic transformations at extreme conditions. Here we report the precise determination of its equation of state and a deep analysis of the evolution of the polyhedral units under compression, thanks to the agreement between our experiments and ab-initio simulations. Our results indicate that this material, with remarkable magnetic properties, is stable at pressures up to 27 GPa. Above 27 GPa, a volume collapse has been observed and ascribed to a change of the local environment of the tetrahedrally coordinated iron towards an octahedral coordination, finding evidence for a different iron oxide polymorph.

Structural and vibrational properties of corundum-type In2O3 nanocrystals under compression.

This work reports the structural and vibrational properties of nanocrystals of corundum-type In2O3 (rh-In2O3) at high pressures by using angle-dispersive x-ray diffraction and Raman scattering measurements up to 30 GPa. The equation of state and the pressure dependence of the Raman-active modes of the corundum phase in nanocrystals are in good agreement with previous studies on bulk material and theoretical simulations on bulk rh-In2O3. Nanocrystalline rh-In2O3 showed stability under compression at least up to 20 GPa, unlike bulk rh-In2O3 which gradually transforms to the orthorhombic Pbca (Rh2O3-III-type) structure above 12-14 GPa. The different stability range found in nanocrystalline and bulk corundum-type In2O3 is discussed.

Arsenolite: a quasi-hydrostatic solid pressure-transmitting medium.

This study reports the experimental characterization of the hydrostatic properties of arsenolite (As4O6), a molecular solid which is one of the softest minerals in the absence of hydrogen bonding. The high compressibility of arsenolite and its stability up to 15 GPa have been proved by x-ray diffraction measurements, and the progressive loss of hydrostaticity with increasing pressure up to 20 GPa has been monitored by ruby photoluminescence. Arsenolite has been found to exhibit hydrostatic behavior up to 2.5 GPa and a quasi-hydrostatic behavior up to 10 GPa at room temperature. This result opens the way to explore other molecular solids as possible quasi-hydrostatic pressure-transmitting media. The validity of arsenolite as an insulating, stable, non-penetrating and quasi-hydrostatic medium is explored by the study of the x-ray diffraction of zeolite ITQ-29 at high pressure.

Pressure-induced phase transformation in zircon-type orthovanadate SmVO4 from experiment and theory.

The compression behavior of zircon-type samarium orthovanadate, SmVO4, has been investigated using synchrotron-based powder x-ray diffraction and ab initio calculations of up to 21 GPa. The results indicate the instability of ambient zircon phase at around 6 GPa, which transforms to a high-density scheelite-type phase. The high-pressure phase remains stable up to 21 GPa, the highest pressure reached in the present investigations. On pressure release, the scheelite phase is recovered. The crystal structure of the high-pressure phase and the equations of state for the zircon- and scheelite-type phases have been determined. Various compressibilities, such as the bulk, axial and bond compressibilities, estimated from the experimental data are found to be in good agreement with the results obtained from theoretical calculations. The calculated elastic constants show that the zircon structure becomes mechanically unstable beyond the transition pressure. Overall there is good agreement between the experimental and theoretical findings.

Pressure-induced amorphization of YVO4:Eu³âº nanoboxes.

A structural transformation from the zircon-type structure to an amorphous phase has been found in YVO4:Eu(3+) nanoboxes at high pressures above 12.7 GPa by means of x-ray diffraction measurements. However, the pair distribution function of the high-pressure phase shows that the local structure of the amorphous phase is similar to the scheelite-type YVO4. These results are confirmed both by Raman spectroscopy and Eu(3+) photoluminescence which detect the phase transition to a scheelite-type structure at 10.1 and 9.1 GPa, respectively. The irreversibility of the phase transition is observed with the three techniques after a maximum pressure in the upstroke of around 20 GPa. The existence of two (5)D0-->(7)F0 photoluminescence peaks confirms the existence of two local environments for Eu(3+), at least for the low-pressure phase. One environment is the expected for substituting Y(3+) and the other is likely a disordered environment possibly found at the surface of the nanoboxes.

Experimental and theoretical study of α-Eu2(MoO4)3 under compression.

The compression process in the α-phase of europium trimolybdate was revised employing several experimental techniques. X-ray diffraction (using synchrotron and laboratory radiation sources), Raman scattering and photoluminescence experiments were performed up to a maximum pressure of 21 GPa. In addition, the crystal structure and Raman mode frequencies have been studied by means of first-principles density functional based methods. Results suggest that the compression process of α-Eu2(MoO4)3 can be described by three stages. Below 8 GPa, the α-phase suffers an isotropic contraction of the crystal structure. Between 8 and 12 GPa, the compound undergoes an anisotropic compression due to distortion and rotation of the MoO4 tetrahedra. At pressures above 12 GPa, the amorphization process starts without any previous occurrence of a crystalline-crystalline phase transition in the whole range of pressure. This behavior clearly differs from the process of compression and amorphization in trimolybdates with [Formula: see text]-phase and tritungstates with α-phase.

Microarray analysis of neonatal rat anteroventral periventricular transcriptomes identifies the proapoptotic Cugbp2 gene as sex-specific and regulated by estradiol.

Sexually dimorphic neural structures regulate numerous gender-specific functions including luteinizing hormone (LH) release patterns. The female cyclic surge pattern of release is controlled by the anteroventral periventricular nucleus (AVPV), a preoptic area (POA) region that is significantly smaller in males. The prevailing hypothesis used to explain these differences in structure and function is that a "default" feminine AVPV is defeminized by exposure to estradiol (E2), a metabolite of testosterone (T) produced by the perinatal testes. E2 exposure then culminates in apoptosis in the male AVPV, but the upstream pathways are poorly understood. To address this issue, we compared AVPV transcriptomes of postnatal day 2 (PND2) males and females with those of females treated with E2 or vehicle. Only six of 89 sex-specific genes were also regulated by E2 in the PND2 AVPV and E2 regulated over 280 genes not found to be sex-specific. Of targets that changed similarly in males and E2-treated females, the gene encoding CUG triplet repeat, RNA-binding protein 2 (Cugbp2), a proapoptotic protein, showed the highest fold-changes. Quantitative polymerase chain reaction (QPCR) studies confirmed higher mRNA levels in PND2 male and E2-treated female AVPVs wherein E2 induces apoptosis. POA mapping studies detected Cugbp2 mRNA in the AVPV and in the sexually dimorphic nucleus of the POA (SDN-POA); however, sex differences and E2 effects occurred only in the AVPV. Combined with evidence that Cugbp2 regulates splicing and translation of mRNAs linked to sexual differentiation, we propose that this gene mediates E2-dependent effects on AVPV defeminization.

Pressure effects on the vibrational properties of α-Bi(2)O(3): an experimental and theoretical study.

We report an experimental and theoretical high-pressure study of the vibrational properties of synthetic monoclinic bismuth oxide (α-Bi(2)O(3): ), also known as mineral bismite. The comparison of Raman scattering measurements and theoretical lattice-dynamics ab initio calculations is key to understanding the complex vibrational properties of bismite. On one hand, calculations help in the symmetry assignment of phonons and to discover the phonon interactions taking place in this low-symmetry compound, which shows considerable phonon anticrossings; and, on the other hand, measurements help to validate the accuracy of first-principles calculations relating to this compound. We have also studied the pressure-induced amorphization (PIA) of synthetic bismite occurring around 20 GPa and showed that it is reversible below 25 GPa. Furthermore, a partial temperature-induced recrystallization (TIR) of the amorphous sample can be observed above 20 GPa upon heating to 200°C, thus evidencing that PIA at room temperature occurs because of the inability of the α phase to undergo a phase transition to a high-pressure phase. Raman scattering measurements of the TIR sample at room temperature during pressure release have been performed. The interpretation of these results in the light of ab initio calculations of the candidate phases at high pressures has allowed us to tentatively attribute the TIR phase to the recently found high-pressure hexagonal HPC phase and to discuss its lattice dynamics.

Investigation of lattice dynamical and dielectric properties of MgO under high pressure by means of mid- and far-infrared spectroscopy.

We investigate the lattice dynamical and dielectric properties of MgO single crystals and powders by measurements in the mid- and far-infrared frequency region under high pressures, ranging up to 21.7 GPa. The shift of the restrahlen region is used to determine the pressure dependence of the transverse and longitudinal optical modes. The analysis of the refractive index in the mid- and far-infrared region allowed us to obtain the pressure behavior of the static and electronic dielectric constants. The transverse effective charge slowly decreases under high pressure, reflecting the stability of MgO. As a consequence, the pressure dependence of the static and electronic dielectric constants is mainly determined by the pressure dependence of the polar phonon frequency and Penn gap, resulting in a pronounced decrease of the former and a moderate decrease of the latter.

Structural study of α-Bi2O3 under pressure.

An experimental and theoretical study of the structural properties of monoclinic bismuth oxide (α-Bi2O3) under high pressures is here reported. Both synthetic and mineral bismite powder samples have been compressed up to 45 GPa and their equations of state have been determined with angle-dispersive x-ray diffraction measurements. Experimental results have been also compared with theoretical calculations which suggest the possibility of several phase transitions below 10 GPa. However, experiments reveal only a pressure-induced amorphization between 15 and 25 GPa, depending on sample quality and deviatoric stresses. The amorphous phase has been followed up to 45 GPa and its nature discussed.

Nonclassical progesterone signalling molecules in the nervous system.

Progesterone (P4) regulates a wide range of cognitive, neuroendocrine, neuroimmune and neuroprotective functions. Therefore, it is not surprising that this ovarian hormone acts through multiple receptors. Ever since the 1980s, studies investigating the neural effects of P4 have focused mainly on genomic and nongenomic actions of the classical progestin receptor (PGR). More recently, two groups of nonclassical P4 signalling molecules have been identified: (i) the class II progestin and adipoQ receptor (PAQR) family, which includes PAQR 5, 6, 7, 8 and 9, also called membrane progestin receptor α (mPRα; PAQR7), mPRß (PAQR8), mPRγ (PAQR5), mPRδ (PAQR6) and mPRε (PAQR9), and (ii) the b5-like haeme/steroid-binding protein family, which includes progesterone receptor membrane component 1 (Pgrmc1), Pgrmc2, neudesin and neuferricin. In this review, we describe the structures, neuroanatomical localisation and signalling mechanisms of these molecules. We also discuss gonadotrophin-releasing hormone regulation as an example of a physiological function regulated by multiple progesterone receptors but through different mechanisms.