Human Glial Cells as Innovative Targets for the Therapy of Central Nervous System Pathologies.

In vitro and preclinical in vivo research in the last 35 years has clearly highlighted the crucial physiopathological role of glial cells, namely astrocytes/microglia/oligodendrocytes and satellite glial cells/Schwann cells in the central and peripheral nervous system, respectively. Several possible pharmacological targets to various neurodegenerative disorders and painful conditions have therefore been successfully identified, including receptors and enzymes, and mediators of neuroinflammation. However, the translation of these promising data to a clinical setting is often hampered by both technical and biological difficulties, making it necessary to perform experiments on human cells and models of the various diseases. In this review we will, therefore, summarize the most relevant data on the contribution of glial cells to human pathologies and on their possible pharmacological modulation based on data obtained in post-mortem tissues and in iPSC-derived human brain cells and organoids. The possibility of an in vivo visualization of glia reaction to neuroinflammation in patients will be also discussed.

Egocentric and Allocentric Spatial Memory for Body Parts: A Virtual Reality Study.

Extensive literature elucidated the mechanisms underlying the ability to memorize the positions of objects in space. However, less is known about the impact that objects' features have on spatial memory. The present study aims to investigate differences in egocentric and allocentric object-location memory between hand stimuli depicted in a first-person perspective (1PP) or in a third-person one (3PP). Fifty-two adults encoded spatial positions within a virtual museum environment featuring four square buildings. Each of these buildings featured eight paintings positioned along the walls, with two pictures displayed on each of the four walls. Thirty-two stimuli were employed, which represented pictures of the right hand performing various types of gestures. Half of the stimuli depicted the hand in the 1PP, while the other half depicted the hand in the 3PP. Both free and guided explorations served as encoding conditions. Immediately after that, participants underwent a two-step object-location memory task. Participants were provided with a map of the museum and asked to identify the correct building where the image was located (allocentric memory). Then, they were presented with a schematic representation of the exhibition room divided into four sections and instructed to select the section where they thought the picture was located (egocentric memory). Our findings indicate a memory performance boost associated with egocentric recall, regardless of the perspective of the bodily stimuli. The results are discussed considering the emerging literature on the mnemonic properties of body-related stimuli for spatial memory.

Neuroinflammation in osteoarthritis: From pain to mood disorders.

Osteoarthritis (OA) is the most common form of musculoskeletal disease, and its prevalence is increasing due to the aging of the population. Chronic pain is the most burdensome symptom of OA that significantly lowers patients' quality of life, also due to its frequent association with emotional comorbidities, such as anxiety and depression. In recent years, both chronic pain and mood alterations have been linked to the development of neuroinflammation in the peripheral nervous system, spinal cord and supraspinal brain areas. Thus, mechanisms at the basis of the development of the neuroinflammatory process may indicate promising targets for novel treatment for pain and affective comorbidities that accompany OA. In order to assess the key role of neuroinflammation in the maintenance of chronic pain and its potential involvement in development of psychiatric components, the monoiodoacetate (MIA) model of OA in rodents has been used and validated. In the present commentary article, we aim to summarize up-to-date results achieved in this experimental model of OA, focusing on glia activation and cytokine production in the sciatic nerve, dorsal root ganglia (DRGs), spinal cord and brain areas. The association of a neuroinflammatory state with the development of pain and anxiety- and depression-like behaviors are discussed. Results suggest that cells and molecules involved in neuroinflammation may represent novel targets for innovative pharmacological treatments of OA pain and mood comorbidities.

Prokineticin System Is a Pharmacological Target to Counteract Pain and Its Comorbid Mood Alterations in an Osteoarthritis Murine Model.

Osteoarthritis (OA) is the most prevalent joint disease associated with chronic pain. OA pain is often accompanied by mood disorders. We addressed the role of the Prokineticin (PK) system in pain and mood alterations in a mice OA model induced with monosodium iodoacetate (MIA). The effect of a PK antagonist (PC1) was compared to that of diclofenac. C57BL/6J male mice injected with MIA in the knee joint were characterized by allodynia, motor deficits, and fatigue. Twenty-eight days after MIA, in the knee joint, we measured high mRNA of PK2 and its receptor PKR1, pro-inflammatory cytokines, and MMP13. At the same time, in the sciatic nerve and spinal cord, we found increased levels of PK2, PKR1, IL-1ß, and IL-6. These changes were in the presence of high GFAP and CD11b mRNA in the sciatic nerve and GFAP in the spinal cord. OA mice were also characterized by anxiety, depression, and neuroinflammation in the prefrontal cortex and hippocampus. In both stations, we found increased pro-inflammatory cytokines. In addition, PK upregulation and reactive astrogliosis in the hippocampus and microglia reactivity in the prefrontal cortex were detected. PC1 reduced joint inflammation and neuroinflammation in PNS and CNS and counteracted OA pain and emotional disturbances.

A predictive coding approach to psychedelic virtual-induced hallucinations and creative cognition in aging.

Recent research has investigated the potential of psychedelic substances in treating various neurological and psychiatric disorders. In particular, there has been a growth in studies concerning the intersection of psychedelics, Virtual Reality (VR), and Cognitive Flexibility (CF). Indeed, the use of immersive technology allows the simulation of the perceptual and cognitive effects of psychedelic substances without the potential risks associated with them. CF is strongly associated with creative cognition, a complex cognitive mechanism involved in creative thinking and associated with the prefrontal cortex and the neural networks supporting executive functions, memory, attention, and spontaneous modes of thought. The Bayesian brain approach, which is rooted in predictive coding, has emerged as a promising framework for understanding the effects of psychedelic hallucinations on cognitive functioning. Psychedelic substances may enhance creativity by inducing a state of CF, allowing for a wider range of associations and possibilities to be explored and increasing openness to experience. A decline in cognitive abilities, including creative processing and divergent thinking, is observed during the aging process. In particular, studies on Mild Cognitive Impairment (MCI) show poorer performance in executive functions, including CF. The present paper suggests that psychedelic hallucinations induced by VR may help optimize the balance between top-down expectations and bottom-up sensory information. Therefore, enhanced CF and creativity may be crucial during the aging process for maintaining cognitive functions and preventing pathological conditions.

Modulation of Glial Cell Functions by the Gut-Brain Axis: A Role in Neurodegenerative Disorders and Pain Transmission.

Studies on host microbiota and their interactions with the central nervous system (CNS) have grown considerably in the last decade. Indeed, it has been widely demonstrated that dysregulations of the bidirectional gut-brain crosstalk are involved in the development of several pathological conditions, including chronic pain. In addition, the activation of central and peripheral glial cells is also implicated in the pathogenesis and progression of pain and other neurodegenerative disorders. Recent preclinical findings suggest that the gut microbiota plays a pivotal role in regulating glial maturation, morphology and function, possibly through the action of different microbial metabolites, including the most studied short-chain fatty acids (SCFAs). Moreover, altered microbiota composition has been reported in CNS disorders characterized by glial cell activation. In this review, we discuss recent studies showing the role of the gut microbiota and the effects of its depletion in modulating the morphology and function of glial cells (microglia and astrocytes), and we hypothesize a possible role for glia-microbiota interactions in the development and maintenance of chronic pain.

The Brazilian Amazonian rainforest harbors a high diversity of yeasts associated with rotting wood, including many candidates for new yeast species.

This study investigated the diversity of yeast species associated with rotting wood in Brazilian Amazonian rainforests. A total of 569 yeast strains were isolated from rotting wood samples collected in three Amazonian areas (Universidade Federal do Amazonas-Universidade Federal do Amazonas [UFAM], Piquiá, and Carú) in the municipality of Itacoatiara, Amazon state. The samples were cultured in yeast nitrogen base (YNB)-d-xylose, YNB-xylan, and sugarcane bagasse and corncob hemicellulosic hydrolysates (undiluted and diluted 1:2 and 1:5). Sugiyamaella was the most prevalent genus identified in this work, followed by Kazachstania. The most frequently isolated yeast species were Schwanniomyces polymorphus, Scheffersomyces amazonensis, and Wickerhamomyces sp., respectively. The alpha diversity analyses showed that the dryland forest of UFAM was the most diverse area, while the floodplain forest of Carú was the least. Additionally, the difference in diversity between UFAM and Carú was the highest among the comparisons. Thirty candidates for new yeast species were obtained, representing 36% of the species identified and totaling 101 isolates. Among them were species belonging to the clades Spathaspora, Scheffersomyces, and Sugiyamaella, which are recognized as genera with natural xylose-fermenting yeasts that are often studied for biotechnological and ecological purposes. The results of this work showed that rotting wood collected from the Amazonian rainforest is a tremendous source of diverse yeasts, including candidates for new species.

Modulation of Glia Activation by TRPA1 Antagonism in Preclinical Models of Migraine.

Preclinical data point to the contribution of transient receptor potential ankyrin 1 (TRPA1) channels to the complex mechanisms underlying migraine pain. TRPA1 channels are expressed in primary sensory neurons, as well as in glial cells, and they can be activated/sensitized by inflammatory mediators. The aim of this study was to investigate the relationship between TRPA1 channels and glial activation in the modulation of trigeminal hyperalgesia in preclinical models of migraine based on acute and chronic nitroglycerin challenges. Rats were treated with ADM_12 (TRPA1 antagonist) and then underwent an orofacial formalin test to assess trigeminal hyperalgesia. mRNA levels of pro- and anti-inflammatory cytokines, calcitonin gene-related peptide (CGRP) and glia cell activation were evaluated in the Medulla oblongata and in the trigeminal ganglia. In the nitroglycerin-treated rats, ADM_12 showed an antihyperalgesic effect in both acute and chronic models, and it counteracted the changes in CGRP and cytokine gene expression. In the acute nitroglycerin model, ADM_12 reduced nitroglycerin-induced increase in microglial and astroglial activation in trigeminal nucleus caudalis area. In the chronic model, we detected a nitroglycerin-induced activation of satellite glial cells in the trigeminal ganglia that was inhibited by ADM_12. These findings show that TRPA1 antagonism reverts experimentally induced hyperalgesia in acute and chronic models of migraine and prevents multiple changes in inflammatory pathways by modulating glial activation.

Flavonoids bridging the gut and the brain: Intestinal metabolic fate, and direct or indirect effects of natural supporters against neuroinflammation and neurodegeneration.

In recent years, experimental evidence suggested a possible role of the gut microbiota in the onset and development of several neurodegenerative disorders, such as AD and PD, MS and pain. Flavonoids, including anthocyanins, EGCG, the flavonol quercetin, and isoflavones, are plant polyphenolic secondary metabolites that have shown therapeutic potential for the treatment of various pathological conditions, including neurodegenerative diseases. This is due to their antioxidant and anti-inflammatory properties, despite their low bioavailability which often limits their use in clinical practice. In more recent years it has been demonstrated that flavonoids are metabolized by specific bacterial strains in the gut to produce their active metabolites. On the other way round, both naturally-occurring flavonoids and their metabolites promote or limit the proliferation of specific bacterial strains, thus profoundly affecting the composition of the gut microbiota which in turn modifies its ability to further metabolize flavonoids. Thus, understanding the best way of acting on this virtuous circle is of utmost importance to develop innovative approaches to many brain disorders. In this review, we summarize some of the most recent advances in preclinical and clinical research on the neuroinflammatory and neuroprotective effects of flavonoids on AD, PD, MS and pain, with a specific focus on their mechanisms of action including possible interactions with the gut microbiota, to emphasize the potential exploitation of dietary flavonoids as adjuvants in the treatment of these pathological conditions.

[The FRASNET study: identification of clinical and social factors of renal failure in an elderly population].

Background. Chronic renal failure is an epidemic in elderly patients. Older population have an increased prevalence of frailty and sarcopenia, associated with a wide range of adverse health outcomes such as falls, hospitalization, disability. Aim. Describe the sociodemographic and clinical variables of an elderly Lombard population and identify predictors of renal insufficiency. Materials and methods. Cross-sectional observational study conducted in hospitals, in recreational centers for the elderly, in the Universities of the Third Age of the provinces of Milan and Monza-Brianza conducted through a convenience sampling of 1250 subjects over the age of 65. Results. The study identified living alone, annual individual income < € 10,000, polypharmacy, sarcopenia and frailty as predictors of chronic kidney failure. The sample has a mean eGFR of 71.74 mL/min/1.73m2 (SD ± 16.56). Older people living alone are more likely to develop CRI (P = 0.031, confidence interval, CI [1.031-1.905]) as well as having an income < € 10,000 (P = 0.002, CI [0.392-0.923]). Taking more than 11 drugs a day increases the probability of having chronic renal failure by 16 times (P = 0.012, CI [1.155-3.16]). Sarcopenia and frailty increase the likelihood of having chronic renal failure (CRI) (P = 0.001, CI [1.198-2.095]). Conclusions. Identifying predictors of chronic kidney failure is a key step in introducing preventive measures and providing better care to the elderly population.

Serum concentrations of free indoxyl and p-cresyl sulfate are associated with mineral metabolism variables and cardiovascular risk in hemodialysis patients.

BACKGROUND: Indoxyl sulfate (IS) and p-cresyl sulfate (PCS) are uremic toxins associated with cardiovascular outcome in CKD patients. The present work is an analysis of the association of serum free, total IS and PCS with cardiovascular events and calcium-phosphate metabolism variables in hemodialysis patients. METHODS: Serum levels of total and free IS and PCS were measured in 139 hemodialysis patients. Their relationship with calcium-phosphate metabolism variables were tested in an observational cohort study. In addition, their association with cardiovascular events was investigated during a 4-year follow-up. RESULTS: Patients in the highest tertile (T3) of serum free IS showed lower serum 1,25(OH)2D compared to patients in the middle (T2) and lowest tertile (T1); in addition to this, T3 patients showed lower serum irisin than T1 patients and lower serum PTH than all the other subjects (T1 + T2) combined. Serum PTH was also measured during the two years after the baseline measurement and was higher in patients in the T1 than in those in the T3 of serum free IS. Cox regression analysis showed that cardiovascular risk was lower in T1 patients than in those in the T3 of serum free PCS, both using a univariate (OR 2.55, 95% CI 1.2-5.43; p = 0.015) or multivariate model (OR 2.48, 95% CI 1.12-5.51; p = 0.003). CONCLUSIONS: Serum free IS may be associated with PTH and 1,25(OH)2D secretion, whereas free PCS may predict cardiovascular risk in hemodialysis patients.

Serum Irisin May Predict Cardiovascular Events in Elderly Patients With Chronic Kidney Disease Stage 3-5.

OBJECTIVE: Irisin is a circulating myokine released from skeletal muscles after physical exercise. Irisin production decreases during the course of chronic kidney disease (CKD) as a potential consequence of sarcopenia and physical inactivity. METHODS: This observational study explored the relationship of serum irisin with cardiovascular outcome in 79 patients with stage 3-5 CKD. RESULTS: Serum irisin was significantly higher in healthy subjects (n = 20) than that in CKD patients (7 ± 2 vs. 3.1 ± 0.9 µg/mL; P = .0001) and was higher in patients with CKD stage 3 (3.2 ± 1 µg/mL) than in patients at stage 4 and 5 taken together (n = 36, 2.8 ± 0.7 µg/mL, P = .05). Patients in the lowest serum irisin tertile had lower serum 1,25(OH)2D levels (21 ± 11 pg/mL) than patients in the middle (30 ± 13 pg/mL; P = .005) and the highest tertile (27 ± 14 pg/mL; P = .047). Patients in the highest tertile had lower Kauppila score (10.6 ± 6.9) than patients in the middle (11.8 ± 5.5; P = .007) and the lowest tertile (6.9 ± 6.8; P = .043). Twenty patients suffered from cardiovascular events during a 3-year follow-up. A Cox regression model using age, body weight, presence of diabetes mellitus, gender, Kauppila calcification score, serum values of FGF23 (as logarithm), phosphate, sclerostin, albumin and cholesterol, estimated glomerular filtration rate, and serum irisin tertiles as covariates showed that patients in the highest tertile of serum irisin had a lower cardiovascular risk than patients in the middle tertile (B, 2.38; odds ratio, 10.8; 95% confidence interval, 1.65-58.13; P = .013) or in the lowest tertile (B, 1.61; odds ratio, 5; 95% confidence interval, 1.09-22.83; P = .038). CONCLUSIONS: These findings suggest that serum irisin may be a marker of cardiovascular outcome in patients with CKD.

Role of blood pressure dysregulation on kidney and mortality outcomes in COVID-19. Kidney, blood pressure and mortality in SARS-CoV-2 infection.

BACKGROUND: In February 2020 the corona virus disease 2019 (COVID-19) infection started spreading throughout Italy, hitting the Lombardy region very hard. Despite the high diffusion, only a subset of patients developed severe COVID-19: around 25% of them developed acute kidney injury (AKI) and one-third of them died. Elderly patients and patients with high comorbidities were identified as being at higher risk of severe COVID-19. METHODS: Our prospective observational cohort study includes 392 consecutive patients hospitalized for COVID-19 in Milan (median age 67 years, 75% male). We evaluated the relationship between blood pressure at presentation, presence of AKI at Emergency Department admission and during hospitalization, and total in-hospital mortality (24%). RESULTS: Although 58% of our study patients reported a history of hypertension (HYP) (86% on treatment), 30% presented with low blood pressure levels. Only 5.5% were diagnosed with AKI on admission; 75% of hypertensive patients discontinued therapy during hospitalization (only 20% were on treatment at discharge). Gender and hypertension were strongly associated with AKI at admission (odds ratio 11). Blood pressure was inversely correlated with increased risk of AKI upon admission, regardless of the severity of respiratory distress. Age over 65, history of hypertension, and severity of respiratory distress were the main predictors of AKI, which developed in 34.7% of cases during hospitalization. AKI was associated with increased in-hospital mortality. Hypertension and low blood pressure at presentation were the main predictors of in-hospital mortality, together with age over 65, baseline pulmonary involvement, and severity of illness. CONCLUSIONS: In patients hospitalized for COVID-19, hypertension and low blood pressure at presentation are important risk factors for AKI and mortality. Early reduction of antihypertensive therapy may improve outcomes in patients with SARS-CoV-2 infection.

Renal tubular acidosis (rta) and kidney stones: diagnosis and Management / Acidosis tubular renal (ATR) y litiasis renal: Diagnóstico y manejo

Renal tubular acidosis (RTA) is a set of rare disorders in which the renal tubule is unable to excrete acid normally and thereby maintain normal acid-base balance, resulting in a complete or incomplete metabolic acidosis. In distal RTA (dRTA, also known as classical or type 1 RTA), there is a defect in excreting H+ ions along the distal nephron (distal tubule and collecting duct), leading to an alkaline urinary pH with calcium phosphate precipitation and stones. Causes of dRTA include genetic mutations, autoimmune disease, and some drugs. Clinical manifestations of the genetic forms of dRTA typically occur during childhood and may vary from mild clinical symptoms, such as a mild metabolic acidosis, hypokalaemia, and incidental detection of kidney stones, to more serious manifestations such as failure to thrive, severe metabolic acidosis, rickets and nephrocalcinosis. Progressive hearing loss may develop in patients with recessive dRTA, which, depending the causative gene mutation, can be present at birth or develop later in adolescence or early adulthood. Diagnosis of dRTA can be challenging, since it requires a high index of suspicion and/or measurement of urinary pH after an acid load, usually in the form of oral ammonium chloride; this should normally acidify the urine to pH below 5.3. In dRTA, urinary citrate levels are also low and patients are at increased risk of forming kidney stones from a combination of alkaline urine and low citrate. Ideally, affected patients need regular outpatient follow-up by a urologist and nephrologist. Thus, any patient found to have a calcium phosphate kidney stone, low urinary citrate, and raised urinary pH, especially with an early morning pH > 5.5, should be evaluated for underlying dRTA. Patients with complete dRTA will have a low (< 20 mmol/L) plasma or serum bicarbonate concentration, whereas in those with incomplete dRTA, bicarbonate levels are usually normal. Oral alkali as potassium citrate is still the mainstay of treatment in dRTA

La acidosis tubular renal (ATR) es un conjunto de enfermedades raras en las que el túbulo renal es incapaz de excretar ácido de forma normal y por ello de mantener un balance ácido-base normal, resultando en una acidosis metabólica completa o incompleta. En la ATR distal (ATRd, también conocida como ATR tipo 1 o clásica), hay un defecto en la excreción de iones H+ a lo largo de la parte distal de la nefrona (túbulo distal y tubo colector) que conduce a un pH urinario alcalino con precipitación de fosfato cálcico y litiasis. Las causas de la ATRd incluyen mutaciones genéticas, enfermedad autoinmune y algunos fármacos. Las manifestaciones clínicas de la forma genética de la ATRd ocurren típicamente durante la infancia y pueden variar desde síntomas leves, como acidosis metabólica leve, hipokaliemia y detección accidental de litiasis renal, hasta manifestaciones más graves tales como falta de crecimiento, acidosis metabólica severa, raquitismo y nefrocalcinosis. En pacientes con ATRd recesiva puede desarrollarse una pérdida progresiva de audición que, dependiendo de la causa de la mutación genética, puede estar presente en el momento del nacimiento o desarrollarse más tarde en la adolescencia o edad adulta temprana. El diagnóstico de la ATRd puede ser un reto ya que requiere un alto grado de sospecha y/o la medición del pH urinario tras una carga ácida, normalmente en forma de cloruro amónico oral; esto debería normalmente acidificar la orina a un pH inferior a 5,3. En la ATRd, los niveles de citrato urinario también son bajos y los pacientes tienen un mayor riesgo de formar litiasis renal por una combinación de orina alcalina e hipocitraturia. Lo ideal es que los pacientes afectados sean seguidos de forma regular por un urólogo y un nefrólogo. Así, cualquier paciente con litiasis de fosfato cálcico, hipocitraturia y pH urinario elevado, especialmente con un pH urinario matutino >5,5, debería ser estudiado para descartar una ATRd oculta. Los pacientes con ATRd completa tendrán una concentración plasmática o sérica de bicarbonato baja (< 20 mmol/L), mientras que en aquellos con una ATRd incompleta, los niveles de bicarbonato son generalmente normales. Los alcalinizantes orales como el citrato potásico son aún el principal pilar del tratamiento en la ATRd

Renal tubular acidosis (RTA) and kidney stones: Diagnosis and management. / Acidosis tubular renal (ATR) y litiasis renal: Diagnóstico y manejo.

Renal tubular acidosis (RTA) is a set of raredis orders in which the renal tubule is unable to excreteacid normally and there by maintain normal acid-basebalance, resulting in a complete or incomplete metabolicacidosis. In distal RTA (dRTA, also known as classicalor type 1 RTA), there is a defect in excreting H+ ionsalong the distal nephron (distal tubule and collectingduct), leading to an alkaline urinary pH with calcium phosphate precipitation and stones. Causes of dRTAinclude genetic mutations, autoimmune disease, and some drugs.Clinical manifestations of the genetic forms of dRTA typically occur during childhood and may vary from mildclinical symptoms, such as a mild metabolic acidosis, hypokalaemia,and incidental detection of kidney stones, to more serious manifestations such as failure to thrive,severe metabolic acidosis, rickets and nephrocalcinosis.Progressive hearing loss may develop in patients withrecessive dRTA, which, depending the causative genemutation, can be present at birth or develop later in adolescence or early adulthood. Diagnosis of dRTA can be challenging, since it requires a high index of suspicion and/or measurement of urinary pH after an acid load, usually in the form of oral ammonium chloride; this should normally acidify the urine to pH below 5.3. In dRTA, urinary citrate levels a real so low and patients are at increased risk of for mingkidney stones from a combination of alkaline urine and low citrate. Ideally, affected patients need regular outpatient follow-up by a urologist and nephrologist. Thus, any patient found to have a calcium phosphate kidney stone, low urinary citrate, and raised urinary pH, especially with an early morning pH >5.5, should be evaluated for underlying dRTA. Patients with complete dRTA will have a low (<20 mmol/L) plasma or serum bicarbonate concentration, whereas in those with incomplete dRTA, bicarbonate levels are usually normal. Oral alkali as potassiumcitrate is still the mainstay of treatment in dRTA.

La acidosis tubular renal (ATR) es un conjunto de enfermedades raras en las que el túbulo renal es incapaz de excretar ácido de forma normal y por ello de mantener un balance ácido-base normal, resultando en una acidosis metabólica completa o incompleta. En la ATR distal (ATRd, también conocida como ATR tipo 1 o clásica), hay un defecto en la excreción de iones H+a lo largo de la parte distal de la nefrona (túbulo distal  y tubo colector) que conduce a un pH urinario alcalino con precipitación de fosfato cálcico y litiasis. Las causas de la ATRd incluyen mutaciones genéticas, enfermedad autoinmune y algunos fármacos. Las manifestaciones clínicas de la forma genética de la ATRd ocurren típicamente durante la infancia y pueden variar desde síntomas leves, como acidosis metabólica leve, hipokaliemia y detección accidental de litiasis renal, hasta manifestaciones más graves tales como falta de crecimiento, acidosis metabólica severa, raquitismo y nefrocalcinosis. En pacientes con ATRd recesiva puede desarrollarse una pérdida progresiva de audición que, dependiendo de la causa de la mutación genética, puede estar presente en el momento del nacimientoo desarrollarse más tarde en la adolescencia o edad adulta temprana.El diagnóstico de la ATRd puede ser un reto ya que requiere un alto grado de sospecha y/o la medición del pH urinario tras una carga ácida, normalmente en forma de cloruro amónico oral; esto debería normalmente acidificar la orina a un pH inferior a 5,3. En la ATRd, los niveles de citrato urinario también son bajos y los pacientes tienen un mayor riesgo de formar litiasis renal por una combinación de orina alcalina e hipocitraturia. Lo ideal es que los pacientes afectados sean seguidos de forma regular por un urólogo y un nefrólogo. Así,cualquier paciente con litiasis de fosfato cálcico, hipocitraturia y pH urinario elevado, especialmente con un pH urinario matutino >5,5, debería ser estudiado para descartar una ATRd oculta. Los pacientes con ATRd completa tendrán una concentración plasmática o sérica de bicarbonato baja (<20 mmol/L), mientras que en aquellos con una ATRd incompleta, los niveles de bicarbonato son generalmente normales. Los alcalinizantes orales como el citrato potásico son aún el principal pilar del tratamiento en la ATRd.

Adenosine Signaling in Autoimmune Disorders.

The molecular components of the purinergic system (i.e., receptors, metabolizing enzymes and membrane transporters) are widely expressed in the cells of the immune system. Additionally, high concentrations of adenosine are generated from the hydrolysis of ATP in any "danger" condition, when oxygen and energy availability dramatically drops. Therefore, adenosine acts as a retaliatory metabolite to counteract the nucleotide-mediated boost of the immune reaction. Based on this observation, it can be foreseen that the recruitment with selective agonists of the receptors involved in the immunomodulatory effect of adenosine might represent an innovative anti-inflammatory approach with potential exploitation in autoimmune disorders. Quite surprisingly, pro-inflammatory activity exerted by some adenosine receptors has been also identified, thus paving the way for the hypothesis that at least some autoimmune disorders may be caused by a derailment of adenosine signaling. In this review article, we provide a general overview of the roles played by adenosine on immune cells with a specific focus on the development of adenosine-based therapies for autoimmune disorders, as demonstrated by the exciting data from concluded and ongoing clinical trials.

Glial cell activation and altered metabolic profile in the spinal-trigeminal axis in a rat model of multiple sclerosis associated with the development of trigeminal sensitization.

Trigeminal neuralgia is often an early symptom of multiple sclerosis (MS), and it generally does not correlate with the severity of the disease. Thus, whether it is triggered simply by demyelination in specific central nervous system areas is currently questioned. Our aims were to monitor the development of spontaneous trigeminal pain in an animal model of MS, and to analyze: i) glial cells, namely astrocytes and microglia in the central nervous system and satellite glial cells in the trigeminal ganglion, and ii) metabolic changes in the trigeminal system. The subcutaneous injection of recombinant MOG1-125 protein fragment to Dark Agouti male rats led to the development of relapsing-remitting EAE, with a first peak after 13 days, a remission stage from day 16 and a second peak from day 21. Interestingly, orofacial allodynia developed from day 1 post injection, i.e. well before the onset of EAE, and worsened over time, irrespective of the disease phase. Activation of glial cells both in the trigeminal ganglia and in the brainstem, with no signs of demyelination in the latter tissue, was observed along with metabolic alterations in the trigeminal ganglion. Our data show, for the first time, the spontaneous development of trigeminal sensitization before the onset of relapsing-remitting EAE in rats. Additionally, pain is maintained elevated during all stages of the disease, suggesting the existence of parallel mechanisms controlling motor symptoms and orofacial pain, likely involving glial cell activation and metabolic alterations which can contribute to trigger the sensitization of sensory neurons.

Dipeptidyl peptidase-4 inhibitors and sulfonylureas prevent the progressive impairment of the nigrostriatal dopaminergic system induced by diabetes during aging.

The nigrostriatal dopaminergic system (NDS) controls motor activity, and its impairment during type 2 diabetes (T2D) progression could increase Parkinson's disease risk in diabetics. If so, whether glycemia regulation prevents this impairment needs to be addressed. We investigated whether T2D impairs the NDS and whether dipeptidyl peptidase-4 inhibition (DPP-4i; a clinical strategy against T2D but also neuroprotective in animal models) prevents this effect, in middle-aged mice. Neither T2D (induced by 12 months of high-fat diet) nor aging (14 months) changed striatal dopamine content assessed by high-performance liquid chromatography. However, T2D reduced basal and amphetamine-stimulated striatal extracellular dopamine, assessed by microdialysis. Both the DPP-4i linagliptin and the sulfonylurea glimepiride (an antidiabetic comparator unrelated to DPP-4i) counteracted these effects. The functional T2D-induced effects did not correlate with NDS neuronal/glial alterations. However, aging itself affected striatal neurons/glia, and the glia effects were counteracted mainly by DPP-4i. These findings show NDS functional pathophysiology in T2D and suggest the preventive use of two unrelated anti-T2D drugs. Moreover, DPP-4i counteracted striatal age-related glial alterations suggesting striatal rejuvenation properties.

Basal astrocyte and microglia activation in the central nervous system of Familial Hemiplegic Migraine Type I mice.

BACKGROUND: Gain-of-function missense mutations in the α1A subunit of neuronal CaV2.1 channels, which define Familial Hemiplegic Migraine Type 1 (FHM1), result in enhanced cortical glutamatergic transmission and a higher susceptibility to cortical spreading depolarization. It is now well established that neurons signal to surrounding glial cells, namely astrocytes and microglia, in the central nervous system, which in turn become activated and in pathological conditions can sustain neuroinflammation. We and others previously demonstrated an increased activation of pro-algogenic pathways, paralleled by augmented macrophage infiltration, in both isolated trigeminal ganglia and mixed trigeminal ganglion neuron-satellite glial cell cultures of FHM1 mutant mice. Hence, we hypothesize that astrocyte and microglia activation may occur in parallel in the central nervous system. METHODS: We have evaluated signs of reactive glia in brains from naïve FHM1 mutant mice in comparison with wild type animals by immunohistochemistry and Western blotting. RESULTS: Here we show for the first time signs of reactive astrogliosis and microglia activation in the naïve FHM1 mutant mouse brain. CONCLUSIONS: Our data reinforce the involvement of glial cells in migraine, and suggest that modulating such activation may represent an innovative approach to reduce pathology.