Brain Aquaporin 4 in Hyperammonemia

In liver failure, congenital enzymopathies of the urea cycle, and other disorders, ammonia may not be properly detoxified and thus hyperammonemia ensues. Hyperammonemia is considered one of the main factors leading to cerebral edema and related consequences (increased intracranial pressure, brain herniation, and death). Cerebral edema is a critical component of neurological status impairment in patients with hyperammonemia and hepatic encephalopathy (HE). Although cerebral edema is generally classified as cytotoxic (cellular) and vasogenic (extracellular), both components often coexist in the same patient. Both types of edema can occur in acute hyperammonemia and liver failure with cytotoxic edema being a consequence of astrocytes swelling and vasogenic edema, mainly due to blood-brain barrier (BBB) disruption. It is well known that hyperammonemia is a crucial factor in astrocytes swelling and increased BBB permeability; however, the molecular mechanisms by which ammonia causes these alterations are not completely understood. Aquaporins (water channels) are one of the main pathways leading to water influx into the brain and efflux from the brain; consequently, it is conceivable brain aquaporins disturbances are involved in the pathophysiology of cerebral edema in hyperammonemia and HE. This review summarizes brain aquaporins main functions and distribution, and particularly, the aquaporin 4 (AQP-4) alterations induced under hyperammonemia and acute liver failure (ALF)

Ankylosing Spondylitis: a trade Off of HLA-B27, ERAP, and pathogen interconnections? Focus on Sardinia

The frequency of HLA-B27 in patients with Ankylosing Spondylitis (AS) is over 85%. There are more than 170 recognized HLA-B27 alleles but the majority of them is not sufficiently represented for genetic association studies. So far only two alleles, the HLA-B*2706 in Asia and the HLA-B*2709 in Sardinia, have not been found to be associated with AS. The highly homogenous genetic structure of the Sardinian population has favored the search of relevant variants for disease-association studies. Moreover, malaria, once endemic in the island, has been shown to have contributed to shape the native population genome affecting the relative allele frequency of relevant genes. In Sardinia, the prevalence of HLA-B*2709, which differs from the strongly AS-associated B*2705 prototype for one amino acid (His/Asp116) in the F pocket of the peptide binding groove, is around 20% of all HLA-B27 alleles. We have previously hypothesized that malaria could have contributed to the establishment of this allele in Sardinia. Based on our recent findings, in this perspective article we speculate that the Endoplasmic Reticulum Amino Peptidases, ERAP1 and 2, associated with AS and involved in antigen presentation, underwent co-selection by malaria. These genes, besides shaping the immunopeptidome of HLA-class I molecules, have other biological functions that could also be involved in the immunosurveillance against malaria

Psoriatic arthritis: genetics and pathogenesis

Psoriatic arthritis is a complex disease affecting primarily peripheral and axial joints and entheses together with the skin. The pathogenesis is characterized by a genetic background and by inflammatory mechanisms which may be triggered by environmental factors. Several susceptibility genes have been investigated; they include HLA genes, genes within the HLA region and genes outside the HLA region. T cells, including the recently described subset Th17, are thought to play an important role in the acute and chronic phases of the disease. Some of these findings allowed novel therapeutic interventions or opened new promising approaches in treatment. The most relevant data of the literature are summarized and discussed

Revisiting the Role of Neurons in Neurovascular Coupling

In this article, we will review molecular, anatomical, physiological and pharmacological data in an attempt to better understand how excitatory and inhibitory neurons recruited by distinct afferent inputs to the cerebral cortex contribute to the coupled hemodynamic response, and how astrocytes can act as intermediaries to these neuronal populations. We aim at providing the pros and cons to the following statements that, depending on the nature of the afferent input to the neocortex, (i) different neuronal or astroglial messengers, likely acting in sequence, mediate the hemodynamic changes, (ii) some recruited neurons release messengers that directly alter blood vessel tone, (iii) others act by modulating neuronal and astroglial activity, and (iv) astrocytes act as intermediaries for both excitatory and inhibitory neurotransmitters. We will stress that a given afferent signal activates a precise neuronal circuitry that determines the mediators of the hemodynamic response as well as the level of interaction with surrounding astrocytes

Mechanical Plantar Foot Stimulation in Parkinson's Disease: A Scoping Review

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease in older individuals. Neurorehabilitation-based interventions such as those improving gait are crucial for a holistic approach and to limit falls. Several studies have recently shown that mechanical plantar foot stimulation is a beneficial intervention for improving gait impairment in PD patients. The objective of this scoping review is to evaluate the beneficial effects of this stimulation on gait parameters, and to analyse protocols of foot stimulation and other effects in non-motor symptoms. Relevant articles were searched in the Medline database using Pubmed and Scopus, using the primary search terms 'foot stimulation' OR 'plantar stimulation' AND 'Parkinson's disease*'. Several protocols have been used for mechanical plantar foot stimulation (ranging from medical devices to textured insoles). The gait parameters that have been shown to be improved are stride length and walking speed. The beneficial effects are achieved after both acute and repeated plantar foot stimulation. Beneficial effects are observed in other organs and systems, such as muscle activation, brain connectivity, cardiovascular control in the central nervous system, and the release of brain-derived neurotrophic factor and cortisol in blood added evidence about this intervention's impact on brain function. Mechanical plantar foot stimulation is a safe and effective add-on treatment able for improving gait impairments in PD patients during the L-dopa off state. Randomized and controlled clinical trials to study its eventual potentiating effect with different pharmacotherapy regimens are warranted

Failure to achieve lupus low disease activity state (LLDAS) six months after diagnosis is associated with early damage accrual in Caucasian patients with systemic lupus erythematosus

Background: The aim was to assess the attainability and outcome of the lupus low disease activity state (LLDAS) in the early stages of systemic lupus erythematosus (SLE). Methods: LLDAS prevalence was evaluated at 6 (T1) and 18 (T2) months after diagnosis and treatment initiation (T0) in a monocentric cohort of 107 (median disease duration 9.7 months) prospectively followed Caucasian patients with SLE. Reasons for failure to achieve LLDAS were also investigated. Multivariate models were built to identify factors associated with lack of LLDAS achievement and to investigate the relationship between LLDAS and Systemic Lupus International Collaboration Clinics (SLICC)/Damage Index (SDI) accrual. Results: There were 47 (43.9%) patients in LLDAS at T1 and 48 (44.9%) at T2. The most frequent unmet LLDAS criterion was prednisolone dose >7.5 mg/day (83% of patients with no LLDAS at T1). Disease manifestations with the lowest remission rate during follow up were increased anti-double-stranded DNA (persistently present in 85.7% and 67.5% of cases at T1 and T2, respectively), low serum complement fractions (73.2% and 66.3%) and renal abnormalities (46.4% and 28.6%). Renal involvement at T0 was significantly associated with failure to achieve LLDAS both at T1 (OR 7.8, 95% CI 1.4-43.4; p = 0.019) and T2 (OR 3.9, 95% CI 1.4-10.6; p = 0.008). Presence of any organ damage (SDI â\u89¥1) at T2 was significantly associated with lack of LLDAS at T1 (OR 5.0, 95% CI 1.5-16.6; p = 0.009) and older age at diagnosis (OR 1.05 per year, 95% CI 1.01-1.09; p = 0.020). Conclusion: LLDAS is a promising treatment target in the early stages of SLE, being attainable and negatively associated with damage accrual, but it fit poorly to patients with renal involvement

Strichartz estimates for the metaplectic representation

We provide new estimates for the matrix coefficients of the metaplectic representation, inspired by a formal analogy with the Strichartz estimates which hold for several classes of evolution propagators U(t). The one parameter group of unitary operators U(t) is replaced by a unitary representation of a non-compact Lie group, the group element playing the role of time; the case of the metaplectic or oscillatory representation is of special interest in this connection, because the Schroedinger group is a subgroup of the metaplectic group. We prove uniform weak-type sharp estimates for matrix coefficients and Strichartz-type estimates for that representation. The crucial point is the choice of function spaces able to detect such a decay, which in general will depend on the given group action. The relevant function spaces here turn out to be the so-called modulation spaces from Time-frequency Analysis in Euclidean space, and Lebesgue spaces with respect to Haar measure on the metaplectic group. The proofs make use in an essential way of the covariance of the Wigner distribution with respect to the metaplectic representation

A survey on sleep assessment methods

[EN] Purpose. A literature review is presented that aims to summarize and compare curren methods to evaluate sleep. Methods. Current sleep assessment methods have been classified according to different. criteria; e.g., objective (polysomnography actigraphy) vs.subjective (sleep questionnaires, diaries...), contact vs. contactless devices, and need for medical assistance vs. self-assessment. A comparison of validation studies is carried out for each method, identifying their sensitivity and specificity reported in the literature. Finally, the state of the market has also been reviewed with respect to customers' opinions about current sleep apps. Results. A taxonomy that classifies the sleep, detection methods. IA deseriPtion of each method that includes the tendencies of their underlying technologies lanalyzed in accordance with the literature. A comparison in terms, of precision of existing validation studies and reports. Discussion. In order of accuracy, sleep detection methods may be arranged as follows: Questionnaire < Sleep diary < Contactless devices < Contact devices < Polysotnnography A literature review suggests that current subjective methods present a sensitivity between 73% and 97.7%, while their specificity ranges in the interval 50%-96%. Objective methods such as actigraphy present a sensibility higher than 90%. However, their specificity is low compared to their sensitivity, being one of the limitations of such technology. Moreover, there are other factors, such as the Patients Perception of her or his sleep, that can be provided only by subjective methods. Therefore, sleep detection methods should be combined to produce a synergy between objective and subjective methods. 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An allelic variant in the intergenic region between ERAP1 and ERAP2 correlates with an inverse expression of the two genes

The Endoplasmatic Reticulum Aminopeptidases ERAP1 and ERAP2 are implicated in a variety of immune and non-immune functions. Most studies however have focused on their role in shaping the HLA class I peptidome by trimming peptides to the optimal size. Genome Wide Association Studies highlighted non-synonymous polymorphisms in their coding regions as associated with several immune mediated diseases. The two genes lie contiguous and oppositely oriented on the 5q15 chromosomal region. Very little is known about the transcriptional regulation and the quantitative variations of these enzymes. Here, we correlated the level of transcripts and proteins of the two aminopeptidases in B-lymphoblastoid cell lines from 44 donors harbouring allelic variants in the intergenic region between ERAP1 and ERAP2. We found that the presence of a G instead of an A at SNP rs75862629 in the ERAP2 gene promoter strongly influences the expression of the two ERAPs with a down-modulation of ERAP2 coupled with a significant higher expression of ERAP1. We therefore show here for the first time a coordinated quantitative regulation of the two ERAP genes, which can be relevant for the setting of specific therapeutic approaches