La planificación económica : un análisis del esquema del Ing. Guido di Tella

Fil: Groppa, Víctor S. Universidad de Buenos Aires. Facultad de Derecho. Cátedra de Política Económica Argentina. Buenos Aires, Argentin

Bi-allelic JAM2 Variants Lead to Early-Onset Recessive Primary Familial Brain Calcification.

Primary familial brain calcification (PFBC) is a rare neurodegenerative disorder characterized by a combination of neurological, psychiatric, and cognitive decline associated with calcium deposition on brain imaging. To date, mutations in five genes have been linked to PFBC. However, more than 50% of individuals affected by PFBC have no molecular diagnosis. We report four unrelated families presenting with initial learning difficulties and seizures and later psychiatric symptoms, cerebellar ataxia, extrapyramidal signs, and extensive calcifications on brain imaging. Through a combination of homozygosity mapping and exome sequencing, we mapped this phenotype to chromosome 21q21.3 and identified bi-allelic variants in JAM2. JAM2 encodes for the junctional-adhesion-molecule-2, a key tight-junction protein in blood-brain-barrier permeability. We show that JAM2 variants lead to reduction of JAM2 mRNA expression and absence of JAM2 protein in patient's fibroblasts, consistent with a loss-of-function mechanism. We show that the human phenotype is replicated in the jam2 complete knockout mouse (jam2 KO). Furthermore, neuropathology of jam2 KO mouse showed prominent vacuolation in the cerebral cortex, thalamus, and cerebellum and particularly widespread vacuolation in the midbrain with reactive astrogliosis and neuronal density reduction. The regions of the human brain affected on neuroimaging are similar to the affected brain areas in the myorg PFBC null mouse. Along with JAM3 and OCLN, JAM2 is the third tight-junction gene in which bi-allelic variants are associated with brain calcification, suggesting that defective cell-to-cell adhesion and dysfunction of the movement of solutes through the paracellular spaces in the neurovascular unit is a key mechanism in CNS calcification

La coparticipación federal de impuestos: una propuesta para salir del actual galimatías

Difficulties to match the political organization of a country with its economic activity become evident in the formulation of its tributary model and particularly in the methods of allocation of its common fiscal resources. In Argentina, the criteria to solve these conflicts have not been the result of an optimizing economic analysis; nor have they been made aiming to overcome regional imbalances. Rather, they have consolidated the status quo, responding to emergency generated disputes. On the other side, there is the risk of proposing solutionsof apparent simplicity and mutual responsibility which imply severe difficulties regarding legal and managing implementation that may generate new asymmetries and conflicts. In this article, the author proposes the elaboration of models of fiscal allocation which harmonize legal technique with economic reality and pursue fairness, efficiency and the responsibility of the actors involved.Las dificultades para compatibilizar la organización política de un país con la actividad económica que en él se desarrolla se manifiestan especialmente en la formulación de su modelo tributario y en particular en los métodos de asignación de los recursos fiscalescomunes. En nuestro país los criterios para resolver estos conflictos no se elaboraron a partir de análisis económicos optimizadores ni con un sentido superador de los desequilibrios regionales. Más bien consolidaron situaciones de hecho, respondiendo a disputas impulsadas por la emergencia. Por otra parte, se corre el riesgo de proponer soluciones de aparente simplicidad y corresponsabilidad, pero que encierran dificultades de instrumentación jurídica y de gestión que pueden generar nuevas asimetrías y conflictos. En este artículo, el autor propone la elaboración de modelos de asignación fiscal que armonicen la técnica jurídica con la realidad económica y procuren la equidad, la eficiencia y la corresponsabilidad de losprotagonistas

Distinct cortical and subcortical structural alterations mirroring daytime‐related seizure occurrence [Abstract]

Purpose: Investigating the daytime‐related patterns of sei-zure presentation might provide important insights into theinvolved epileptogenic networks. However, the alterationsof brain structural integrity linked to different profiles ofseizure occurrence are still not clear. In this study weaddressed the structural magnetic resonance imaging(MRI)‐derived features of the involved cortical and subcor-tical substrates. Method: In 13 patients (mean age ± standard deviation:28±9 years; 9 male) with nocturnal seizures (NS), 12patients (26±9; 3 male) with diurnal seizures (DS) and 10healthy controls (HC) (28±4; 6 male) 3D 3T MRI was per-formed. Cortical and subcortical volumes (hippocampus,amygdala, thalamus) were extracted with the FreeSurferprocessing stream and the between‐group differencesassessed with analysis of variance (ANOVA) and Bonfer-roni post hoc tests. There was no difference between thegroups regarding age (F2,32= 0.26, p = 0.77) and gender(χ†= 5.103, df = 2, p = 0.08). Results: NS group in contrast to DS group showed largervolumes of bilateral insula, superior temporal and orbito-frontal cortices (p = 0.05, corrected). In patients with NScortical volumes of left postcentral and right middle tempo-ral cortices were smaller in comparison to HC. Patientswith DS in comparison to HC displayed reduced corticalvolumes mainly in frontal, temporal and parietal lobes ofthe right hemisphere. Hippocampus analysis showed a sig-nificant group difference (F2,32= 3.643, p = 0.03) withpost hoc test indicating larger volumes in NS group(8208.6±1006.1) vs DS group (3859.1±508.1 mm‡,p = 0.02). For amygdala, ANOVA showed a similar signif-icant group difference (F2,32= 4.341, p = 0.02) with largervolumes in NS group (1797.3±323.2 mm‡) vs DS group(1500.5±246.2 mm‡, p = 0.03). There were no differencesin thalamic volumes between the studied groups. Conclusion: Despite epileptogenesis daytime‐related sei-zures have distinct structural correlates. These alterationscan assign protective or susceptibility properties linked tovigilance or sleep states that could be useful for therapeuticdecisions

Genetic and phenotypic characterization of NKX6‐2‐related spastic ataxia and hypomyelination

Background and purpose Hypomyelinating leukodystrophies are a heterogeneous group of genetic disorders with a wide spectrum of phenotypes and a high rate of genetically unsolved cases. Bi‐allelic mutations in NKX6‐2 were recently linked to spastic ataxia 8 with hypomyelinating leukodystrophy. Methods Using a combination of homozygosity mapping, exome sequencing, and detailed clinical and neuroimaging assessment a series of new NKX6‐2 mutations in a multicentre setting is described. Then, all reported NKX6‐2 mutations and those identified in this study were combined and an in‐depth analysis of NKX6‐2‐related disease spectrum was provided. Results Eleven new cases from eight families of different ethnic backgrounds carrying compound heterozygous and homozygous pathogenic variants in NKX6‐2 were identified, evidencing a high NKX6‐2 mutation burden in the hypomyelinating leukodystrophy disease spectrum. Our data reveal a phenotype spectrum with neonatal onset, global psychomotor delay and worse prognosis at the severe end and a childhood onset with mainly motor phenotype at the milder end. The phenotypic and neuroimaging expression in NKX6‐2 is described and it is shown that phenotypes with epilepsy in the absence of overt hypomyelination and diffuse hypomyelination without seizures can occur. Conclusions NKX6‐2 mutations should be considered in patients with autosomal recessive, very early onset of nystagmus, cerebellar ataxia with hypotonia that rapidly progresses to spasticity, particularly when associated with neuroimaging signs of hypomyelination. Therefore, it is recommended that NXK6‐2 should be included in hypomyelinating leukodystrophy and spastic ataxia diagnostic panels

Effective deep brain stimulation co-modulate cross-frequency coupling [Abstract]

Objective: The disruption of pathological signals in the cortico-basal ganglia- network has been hypothesized as a mechanism of action of deep brain stimulation (DBS). However, a comprehensive model for DBS modulating oscillations is still missing. Background: Besides considering gamma as physiologic and pro-kinetic, it has been suggested that finely tuned gamma oscillations between 60-90Hz reflect dynamic processing, possibly by inducing local inhibition or facilitation. Most studies investigating gamma focused on oscillations within the STN, motor cortex (M1), supplementary motor area (SMA), and the pallidum (Allert et al., 2018). Furthermore, elements of the BG-thalamocortical network like the premotor (PMC) or prefrontal cortices (PFC) and the sub-cortical network of cerebellum (CB) have been neglected to date. Method: We recorded resting state high-density 256-channels EEG of 31 PD-patients during DBS at the clinically most effective frequency (i.e 130Hz or 160Hz). We compared spectral power and cross-frequency coupling (frequency to power) of cortical and subcortical regions using a beamformer algorithm for coherent sources (Muthuraman et al., 2018). Two clinically ineffective frequencies have been tested as control conditions. Results: We demonstrated that clinically effective STN-DBS alters oscillatory activity in a wide-spread network of cortical and subcortical regions. A reduction of beta and increase of gamma power is attested in the cortical (M1, SMA, PMC, PFC) and sub-cortical network nodes (STN, CB). Additionally, we found increased cross-frequency coupling of narrowband gamma frequencies to the stimulation frequency in the same nodes of the cortico-subcortical network. No such dynamics were revealed within control regions (i.e. posterior parietal cortex). Furthermore, stimulating at lower or higher frequencies did not significantly alter the networks’ source power spectra or cross-frequency coupling. Conclusion: We were able to show a modulation of beta- and gamma-power and cross-frequency coupling during DBS with HD-EEG in a cortical-sub cortical network. DBS does not exclusively influence motor-function but also the physiological processing related to facilitation and dynamic adaptation, in line with the proposed function of gamma oscillations

Differentiating Parkinson's disease from advanced essential tremor using EMG [Abstract]

Objective: The primary objective of this study is to find out the appropriate spectral parameter from the electromyography (EMG) signals which quantitatively classify PD from ET tremor. Background: Essential tremor (ET) and the tremor in Parkinson's disease (PD) are the two most common pathological tremor forms encountered in clinical practice. Differential diagnosis between the two tremors is usually achieved clinically. There is a certain overlap in the presentation of these tremor forms while the clinical differentiation on purely clinical grounds might be challenging. Methods: EMG recordings on the more affected side of 194 age (60.84 ± 8.9 years) and sex matched (M=120; F=74) ET and PD patients were analyzed. Postural tremor was recorded from the more affected side, while subjects extended their hands and fingers actively to a 0 ° position with the resting forearm. This posture was held against gravity, and in this condition the tremor was recorded for a period of 30 seconds. The parameters from the power spectra of the EMG were tremor frequency, peak power, number of harmonic peaks, waveform asymmetry (autocorrelation decay), mean peak power of all harmonic peaks, coherence (antagonistic muscles), frequency-frequency coupling, phase-phase coupling and power-power coupling were estimated on the basic and harmonic frequencies. The reliable parameter for the classification was quantified with a support vector machine (SVM) classifier (50% training; 50% testing). Results: Tremor frequency, peak power, number of harmonic peaks showed less than 50% classification accuracy for the testing data. Whereas mean peak power of all harmonics showed 93% classification accuracy for the discrimination (PD>ET), frequency-frequency coupling showed 95% (ET>PD), phase-phase coupling showed 96% (ET>PD), power-power coupling showed 98% (PD>ET) respectively. Conclusions: The relation between the basic and harmonics peak frequencies play a major role in distinguishing ET from PD tremor. The mean peak power of all harmonics and the three coupling estimates are applicable measures to separate by the aid of artificial learning algorithms clinical difficult entities of ET from PD tremor cases with a very high reliability

Linking immune-mediated damage to neurodegeneration in multiple sclerosis: could network-based MRI help?

Inflammatory demyelination characterizes the initial stages of multiple sclerosis, while progressive axonal and neuronal loss are coexisting and significantly contribute to the long-term physical and cognitive impairment. There is an unmet need for a conceptual shift from a dualistic view of multiple sclerosis pathology, involving either inflammatory demyelination or neurodegeneration, to integrative dynamic models of brain reorganization, where, glia-neuron interactions, synaptic alterations and grey matter pathology are longitudinally envisaged at the whole-brain level. Functional and structural MRI can delineate network hallmarks for relapses, remissions or disease progression, which can be linked to the pathophysiology behind inflammatory attacks, repair and neurodegeneration. Here, we aim to unify recent findings of grey matter circuits dynamics in multiple sclerosis within the framework of molecular and pathophysiological hallmarks combined with disease-related network reorganization, while highlighting advances from animal models (in vivo and ex vivo) and human clinical data (imaging and histological). We propose that MRI-based brain networks characterization is essential for better delineating ongoing pathology and elaboration of particular mechanisms that may serve for accurate modelling and prediction of disease courses throughout disease stages

Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination.

Axon pathfinding and synapse formation are essential processes for nervous system development and function. The assembly of myelinated fibres and nodes of Ranvier is mediated by a number of cell adhesion molecules of the immunoglobulin superfamily including neurofascin, encoded by the NFASC gene, and its alternative isoforms Nfasc186 and Nfasc140 (located in the axonal membrane at the node of Ranvier) and Nfasc155 (a glial component of the paranodal axoglial junction). We identified 10 individuals from six unrelated families, exhibiting a neurodevelopmental disorder characterized with a spectrum of central (intellectual disability, developmental delay, motor impairment, speech difficulties) and peripheral (early onset demyelinating neuropathy) neurological involvement, who were found by exome or genome sequencing to carry one frameshift and four different homozygous non-synonymous variants in NFASC. Expression studies using immunostaining-based techniques identified absent expression of the Nfasc155 isoform as a consequence of the frameshift variant and a significant reduction of expression was also observed in association with two non-synonymous variants affecting the fibronectin type III domain. Cell aggregation studies revealed a severely impaired Nfasc155-CNTN1/CASPR1 complex interaction as a result of the identified variants. Immunofluorescence staining of myelinated fibres from two affected individuals showed a severe loss of myelinated fibres and abnormalities in the paranodal junction morphology. Our results establish that recessive variants affecting the Nfasc155 isoform can affect the formation of paranodal axoglial junctions at the nodes of Ranvier. The genetic disease caused by biallelic NFASC variants includes neurodevelopmental impairment and a spectrum of central and peripheral demyelination as part of its core clinical phenotype. Our findings support possible overlapping molecular mechanisms of paranodal damage at peripheral nerves in both the immune-mediated and the genetic disease, but the observation of prominent central neurological involvement in NFASC biallelic variant carriers highlights the importance of this gene in human brain development and function