Pleiotrophin modulates acute and long-term LPS-induced neuroinflammatory responses and hippocampal neurogenesis.

The hippocampus is one of the most vulnerable regions affected in disorders characterized by overt neuroinflammation such as neurodegenerative diseases. Pleiotrophin (PTN) is a neurotrophic factor that modulates acute neuroinflammation in different contexts. PTN is found highly upregulated in the brain in different chronic disorders characterized by neuroinflammation, suggesting an important role in the modulation of sustained neuroinflammation. To test this hypothesis, we studied the acute and long-term effects of a single lipopolysaccharide (LPS; 5 mg/kg) administration in Ptn+/+ and Ptn-/- mice, and in mice with Ptn-overexpression (Ptn-Tg). Endogenous PTN levels proportionally modulate LPS-induced increase in TNF-α plasma levels one hour after treatment. In the dentate gyrus (DG) of the hippocampus, a lower percentage of DCX+ cells were detected in saline-treated Ptn-/- mice compared to Ptn+/+ mice, suggesting a crucial role of PTN in the maintenance of hippocampal neuronal progenitors. The data show that PTN overexpression tends to potentiate acute microglial responses in the DG 16 hours after LPS treatment. Remarkably, a significant increase in the number of neuronal progenitors together with astrogliosis was detected 10 months after a single injection of LPS treatment in wild type mice. However, these LPS-induced long-term effects were prevented in Ptn-/- and Ptn-Tg mice, suggesting that PTN modulates LPS-induced long-term neurogenesis changes and astrocytic response in the hippocampus. The data presented here suggest that endogenous PTN levels are crucial in the regulation of acute LPS-induced systemic and hippocampal microglial responses in young mice. Furthermore, our findings provide evidence of the key role of PTN in the regulation of long-term LPS effects on astrocytic response and neurogenesis in the hippocampus.

Surface and groundwater flow exchanges and lateral hydrological connectivity in environments of the Matusagaratí Wetland, Panama.

The Matusagaratí wetland in the Panamanian Darien is one of the largest wetlands in Central America. These types of riverine wetlands, associated with large drainage basins, are complex hydrological environments where variations in water flows and exchanges condition the existence of different wetland habitats. The work aimed to establish the hydrological functioning of the Matusagaratí wetland in different sectors of the Balsas River, emphasizing the exchanges of surface and groundwater flows and the hydrological connectivity that exists between the different laterally linked wetland environments. For this purpose, a monitoring network for surface water and groundwater was established along transects intersecting various wetland environments in the middle and lower basin of the Balsas River. This network is complemented by measurement points for surface water located in streams and in the upper basin of the river. Data collected in sensors installed in boreholes were compared to river level and precipitation data. Continuous water level recording sensors were installed at the monitoring points, and samples were collected for the determination of major ions and stable isotopes. The results indicate that in the mangroves of the lower basin and in the cativo forests of the middle basin levee there is a strong exchange of water between the river and the shallow groundwater. This water exchange is strongly influenced by the tide which spreads from the estuary to the continent through the river. Meanwhile, in the middle basin, mixed forests and orey forests developed on the alluvial plain exhibit a hydrological functioning that depends primarily on precipitation inputs. This study provides data that could serve as a basis for the management of this large tropical wetland that, despite having protection initiatives, could be hydrologically impacted by unsustainable socio-economic practices.

Implication of the PTN/RPTPß/ζ Signaling Pathway in Acute Ethanol Neuroinflammation in Both Sexes: A Comparative Study with LPS.

Binge drinking during adolescence increases the risk of alcohol use disorder, possibly by involving alterations of neuroimmune responses. Pleiotrophin (PTN) is a cytokine that inhibits Receptor Protein Tyrosine Phosphatase (RPTP) ß/ζ. PTN and MY10, an RPTPß/ζ pharmacological inhibitor, modulate ethanol behavioral and microglial responses in adult mice. Now, to study the contribution of endogenous PTN and the implication of its receptor RPTPß/ζ in the neuroinflammatory response in the prefrontal cortex (PFC) after acute ethanol exposure in adolescence, we used MY10 (60 mg/kg) treatment and mice with transgenic PTN overexpression in the brain. Cytokine levels by X-MAP technology and gene expression of neuroinflammatory markers were determined 18 h after ethanol administration (6 g/kg) and compared with determinations performed 18 h after LPS administration (5 g/kg). Our data indicate that Ccl2, Il6, and Tnfa play important roles as mediators of PTN modulatory actions on the effects of ethanol in the adolescent PFC. The data suggest PTN and RPTPß/ζ as targets to differentially modulate neuroinflammation in different contexts. In this regard, we identified for the first time important sex differences that affect the ability of the PTN/RPTPß/ζ signaling pathway to modulate ethanol and LPS actions in the adolescent mouse brain.

Pleiotrophin deficiency protects against high-fat diet-induced neuroinflammation: Implications for brain mitochondrial dysfunction and aberrant protein aggregation.

Metabolic Syndrome (MetS) is a risk factor for the development of neurodegenerative diseases. Neuroinflammation associated with MetS may contribute significantly to neurodegeneration. Pleiotrophin (PTN) is a neurotrophic factor that modulates neuroinflammation and is a key player in regulating energy metabolism and thermogenesis, suggesting that PTN could be important in the connection between MetS and neuroinflammation. We have now used a high-fat diet (HFD)-induced obesity model in Ptn-/- mice. HFD and Ptn deletion caused alterations in circulating hormones including GIP, leptin and resistin. HFD produced in Ptn+/+ mice a neuroinflammatory state as observed in cerebral quantifications of proinflammatory markers, including Il1ß, Tnfα and Ccl2. The upregulation of neuroinflammatory markers was prevented in Ptn-/- mice. Changes induced by HFD in genes related to mitochondrial biogenesis and dynamics were less pronounced in the brain of Ptn-/- mice and were accompanied by significant increases in the protein expression of mitochondrial oxidative phosphorylation (OXPHOS) complexes I and IV. HFD-induced changes in genes related to the elimination of protein aggregates were also less pronounced in the brain of Ptn-/- mice. This study provides substantial evidence that Ptn deletion protects against HFD-induced neuroinflammation, mitochondrial dysfunction, and aberrant protein aggregation, prominent features in neurodegenerative diseases.

Influence of Diet and Lifestyle on the Development of Gestational Diabetes Mellitus and on Perinatal Results.

GDM is a multifactorial disease, so there is controversy regarding the mechanisms involved in its pathogenesis. We speculate whether lifestyle and eating habits influenced the appearance and pathogenesis of GDM. To explore this issue, the aim of the present study was to analyze maternal diet and lifestyle characteristics in early pregnancy and their influence on the development of GDM. The study included 103 pregnant women who completed a questionnaire on nutritional knowledge, lifestyle and eating habits. Perinatal and biochemical outcomes as well as pregestational lifestyle and eating habits were compared between normoglycemic women and those who developed GDM. The results obtained showed that women who developed GDM had erroneous knowledge regarding nutrition. Consumption of white bread (p = 0.018), added sugars (p = 0.037), legumes (p = 0.025), fish (p = 0.014), butter (p = 0.010) and the performance of less physical activity (p = 0.024) correlated with glucose intolerance in pregnant women. In conclusion, we found a relationship between dietary and lifestyle habits at the beginning of pregnancy and the later diagnosis of GDM.

Hydrochemistry, isotope studies and salt formation in saline lakes of arid regions: Extra-Andean Patagonia, Argentina.

The most favourable locations for the development of saline lakes are in the rain-shadow of mountain ranges, which provide large areas of precipitation catchment while the base of the basin is under arid climate and exposed to evaporation. These conditions are found in Extra-Andean Patagonia under the rain-shadow generated by the Andean cordillera. There, an endorheic basin with two shallow and saline lakes, Cari Laufquen Chica (CLC) and Cari Laufquen Grande (CLG), was studied with the aim of analysing the factors that condition the hydrochemical processes acting in the formation of evaporites associated with these environments. A monitoring network was installed and five surface and groundwater survey campaigns were carried out at different points in the basin to define groundwater flow and also to extract samples. In situ pH, electrical conductivity and temperature and laboratory physicochemical determinations of major ions and stable isotopes of the water were measured. SEM-EDS and XRD analyses of saline crusts from the edge of the lakes and adjacent sediments were carried out. The obtained results allowed identifying that CLC and CLG saline lakes have different surface water-groundwater configurations. CLC is a flow-through shallow lake, while CLG is a discharge shallow lake. The analysis of the saline precipitates and the chemical facies of the water allows identifying cycles of dissolution, evaporation and precipitation in both saline lakes. However, the different groundwater flow between the two lakes is reflected in their salinity as well as in the evolution and development of saline precipitates. CLC saline lake shows a dissolution-precipitation trend of thenardite and Ca-Mg carbonates, whereas CLG saline lake displays a trend of dissolution-precipitation of halite, thenardite and trona with strong dominance of halite. The present study identifies for the first time the main factors conditioning hydrochemical processes in these saline lakes of extra-Andean Patagonia. Our results indicate that the hydrological configuration with respect to the groundwater flow is the prevailing factor setting the hydrochemical processes that trigger the formation of salt crusts.

Pleiotrophin Deficiency Induces Browning of Periovarian Adipose Tissue and Protects against High-Fat Diet-Induced Hepatic Steatosis.

(1) Background: Pleiotrophin preserves insulin sensitivity, regulates adipose tissue lipid turnover and plasticity, energy metabolism and thermogenesis. The aim of this study was to determine the role of pleiotrophin in hepatic lipid metabolism and in the metabolic crosstalk between the liver and brown and white adipose tissue (AT) in a high-fat diet-induced (HFD) obesity mice model. (2) Methods: We analyzed circulating variables, lipid metabolism (hepatic lipid content and mRNA expression), brown AT thermogenesis (UCP-1 expression) and periovarian AT browning (brown adipocyte markers mRNA and immunodetection) in Ptn-/- mice either fed with standard-chow diet or with HFD and in their corresponding Ptn+/+ counterparts. (3) Results: HFD-Ptn-/- mice are protected against the development of HFD-induced insulin resistance, had lower liver lipid content and lower expression of the key enzymes involved in triacylglycerides and fatty acid synthesis in liver. HFD-Ptn-/- mice showed higher UCP-1 expression in brown AT. Moreover, Ptn deletion increased the expression of specific markers of brown/beige adipocytes and was associated with the immunodetection of UCP-1 enriched multilocular adipocytes in periovarian AT. (4) Conclusions: Ptn deletion protects against the development of HFD-induced insulin resistance and liver steatosis, by increasing UCP-1 expression in brown AT and promoting periovarian AT browning.

Role of Receptor Protein Tyrosine Phosphatases (RPTPs) in Insulin Signaling and Secretion.

Changes in lifestyle in developed countries have triggered the prevalence of obesity and type 2 diabetes mellitus (T2DM) in the latest years. Consequently, these metabolic diseases associated to insulin resistance, and the morbidity associated with them, accounts for enormous costs for the health systems. The best way to face this problem is to identify potential therapeutic targets and/or early biomarkers to help in the treatment and in the early detection. In the insulin receptor signaling cascade, the activities of protein tyrosine kinases and phosphatases are coordinated, thus, protein tyrosine kinases amplify the insulin signaling response, whereas phosphatases are required for the regulation of the rate and duration of that response. The focus of this review is to summarize the impact of transmembrane receptor protein tyrosine phosphatase (RPTPs) in the insulin signaling cascade and secretion, and their implication in metabolic diseases such as obesity and T2DM.

Processes controlling groundwater salinity in coastal wetlands of the southern edge of South America.

The Argentine Atlantic coast constitutes an extensive area where numerous wetlands develop under humid, semi-arid and arid conditions, in which there are also variations in relation to tidal influence with estuarine, mixing and marine areas. The aim of this work is to conduct a comparative study on the processes controlling the groundwater salinity in medium to high latitudinal coastal wetlands of four natural reserves with contrasting hydrological and climatic conditions. In each study area a monitoring network was established where the content of CO32-, HCO3-, Cl-, SO42-, Ca2+, Mg2+, Na+, K+, δ2H and δ18O of the water were determined. The results show a saline groundwater increase along a latitudinal gradient with electrical conductivities varying from 0.3 mS/cm at 34°47' S to 154 mS/cm at 42° 25' S. The results obtained show that the ionic contents in groundwater are partially controlled by the salinity of the tidal flood water whose electrical conductivity varies from 0.3 mS/cm in the Río de la Plata estuary to 52 mS/cm in the sea water of the southern study area. In the southern wetlands, where an increase of aridity is also registered, there is a clear increase in groundwater ionic concentrations, which occurs without isotopic enrichment indicating processes of salts dissolution of the sediments. The evaporites precipitation occurs due to the total evaporation of the tidal water that floods the wetlands in spring high tides. The salinization of groundwater responds to natural processes inherent to the hydrological, climatic and lithological characteristics of each wetland. Given that the areas studied correspond to natural reserves, the results generate databases that will allow the identification of future changes in salinity associated with anthropic influences or changes in hydrological and/or climatic conditions as a result of climate change.

Metabolic alterations associated with maternal undernutrition during the first half of gestation lead to a diabetogenic state in the rat.

BACKGROUND: Although recent studies have investigated the effect of maternal nutrition on metabolic programming of the offspring, the question whether a nutritional insult during early gestation favours an altered metabolic state of the mother that persists during the remainder period of pregnancy, when foetal growth is maximal, remains to be answered. METHODS: To address this issue, we analysed the effect of 40% food restriction during the first 12 days of gestation on glucose tolerance, as well as on liver and adipose tissue metabolism, in Sprague-Dawley pregnant rats. RESULTS: We found that undernutrition at early gestation blocks pregnancy-associated accumulation of fat, leading to a net breakdown of lipids that may account for an increased delivery of fatty acids and glycerol to the liver. Together with altered expression of hepatic enzymes, this creates a catabolic state, characterized by decreased lipogenesis and increased ß-oxidation, which contributes to the ketonemia of underfed mothers. Furthermore, we observed that undernutrition during early pregnancy impairs insulin sensitivity at this stage and, importantly, exacerbates insulin resistance at late gestation, contributing to a diabetogenic state. CONCLUSION: Undernutrition during the first half of pregnancy not only alters liver and adipose tissue metabolism, but also exacerbates the maternal insulin resistance at late gestation, which may increase their risk of gestational diabetes. GENERAL SIGNIFICANCE: Together, these findings highlight the persistent impact of maternal nutrition during early gestation on the metabolism of the mother during late pregnancy.

Series de Pediatría Garrahan. El niño con trastornos del neurodesarrollo / Garrahan Pediatrics Series. The child with neurodevelopmental disorders

La infancia es una etapa vital clave, ya que en ella se forman los cimientos que luego determinarán el desarrollo físico y mental de las personas. Por eso, brindar las herramientas necesarias para satisfacer las necesidades y los derechos del niño es fundamental para garantizar la inclusión y la igualdad de oportunidades de todos. El desarrollo del niño conlleva cambios biológicos, psicológicos y emocionales que ocurren desde el nacimiento hasta la adolescencia, a medida que el individuo pasa de la dependencia al aumento de la autonomía. La frecuencia de los trastornos del neurodesarrollo es importante y creciente y el pediatra desempeña un papel crucial en su detección oportuna, asesoría a las familias y estrategias de manejo o derivación para asegurar las mejores posibilidades de prevención y asistencia. Asimismo, la elevada morbilidad pediátrica asociada al concepto de enfermedad crónica requiere una actitud diagnóstica anticipatoria de la disfunción neurocognitiva y madurativa a la que están expuestos estos niños. En este nuevo volumen de las Series de Pediatría Garrahan destacados profesionales estudian la temática del desarrollo desde un abordaje interdisciplinario centrado en el rol del pediatra. Entre sus características se destacan: Presentación mediante casos y ejemplos de la práctica clínica de los trastornos más frecuentes del desarrollo infantil estructurados según las diferentes etapas de lactante, preescolar y escolar, así como el abordaje de la discapacidad intelectual, el impacto de la enfermedad crónica en el aprendizaje y los marcos normativos en educación. El cierre de cada capítulo con un recordatorio de puntos clave y lecturas recomendadas, además del material complementario disponible en el sitio web. Una obra sólida y práctica, que transmite la experiencia de los profesionales del Hospital de Pediatría Prof. Dr. Juan P Garrahan, dedicada a los pediatras, dondequiera que trabajen al servicio de la salud de los niños.

Geochemical processes controlling the distribution and concentration of metals in soils from a Patagonian (Argentina) salt marsh affected by mining residues.

Heavy metal pollution that affects salt marshes is a major environmental concern due to its toxic nature, persistence, and potential risk to organisms and to human health. Mining waste deposits originated four decades ago, by the metallurgical extraction of heavy metals, are found near to the San Antonio salt marsh in Patagonia. The aim of the work was to determine the geochemical processes that control the distribution and concentration of Cu, Fe, Pb and Zn in the soils of this Patagonian salt marsh. A survey of the mining waste deposits was carried out where three dumps were identified. Samples were collected to determine soil texture, Eh pH, organic matter and metal contents and the soil mineralogical composition. The results shows that the soils developed over the mining waste deposits are predominantly reddish constituted mainly by iron oxide, hydroxide and highly soluble minerals such as Zn and Cu sulphates. The drainage from these deposits tends to move towards the salt marsh. Within the salt marsh, the highest concentrations of Cu, Pb and Zn occur in the sectors closest to the mining wastes deposits. The sulphide oxidation and the dissolution of the Cu, Pb and Zn sulphates could be the mainly source of these metals in the drainage water. The metals in solution that reach the salt marsh, are adsorbed by the organic matter and the fine fraction of the soils. These adsorbed metals are then remobilized by tides in the lower sectors of the marsh by desorption from the cations present in the tidal flow. On the other hand, Fe tends to form non soluble oxides, hydroxides and sulphates which remain as altering material within the mining waste deposit. Finally, the heavy metal pollutants recorded in the San Antonio salt marsh shows that the mining waste deposits that were abandoned four decades ago are still a source metal contamination.

Assessment of factors enabling halite formation in a marsh in a humid temperate climate (Ajó Marsh, Argentina).

The formation of evaporites associated with the final stages of the precipitation sequence, such as the case of halite, is frequent in marshes in arid areas, but it is not to be expected in those humid climates. This work, by means of the study of the hydrological, climatic and land use conditions, identifies the factors that allow the formation of saline precipitations in a marsh located in a humid climate area. The results obtained show that the exclusion of the marsh as a result of the embankment is the main reason for the presence of halite. It is to be expected that in the future the growth of the embanked marsh areas, together with the climatic and tidal condition tendencies recorded, will favour a higher rate of formation of evaporite salts. The identification of these factors makes it possible to set basic sustainable management guidelines to avoid soil salinisation.

The role of evapotranspiration in the groundwater hydrochemistry of an arid coastal wetland (Península Valdés, Argentina).

Coastal wetlands are complex hydrogeological systems, in which saline groundwater usually occurs. Salinity can be attributed to many origins, such as dissolution of minerals in the sediments, marine contribution and evapotranspiration, among others. The aim of this paper is to evaluate the processes that condition the hydrochemistry of an arid marsh, Playa Fracasso, located in Patagonia, Argentina. A study of the dynamics and geochemistry of the groundwater was carried out in each hydrogeomorphological unit, using major ion and isotope ((18)O and (2)H) data, soil profiles descriptions and measurements, and recording of water tables in relation to the tidal flow. Water balances and analytical models based on isotope data were used to quantify the evaporation processes and to define the role of evaporation in the chemical composition of water. The results obtained show that the groundwater salinity of the marsh comes mainly from the tidal inflow, to which the halite and gypsum dissolution is added. These mineral facies are the result of the total evaporation of the marine water flooding that occurs mostly at the spring high tides. The isotope relationships in the fan and bajada samples show the occurrence of evaporation processes. Such processes, however, are not mainly responsible for the saline content of groundwater, which is actually generated by the dissolution of the typical evaporite facies of the arid environment sediments. It is concluded that the evapotranspiration processes condition groundwater quality. This is not only due to the saline enrichment caused by the evapotranspiration of shallow water, but also because such processes are the main drivers of the formation of soluble salts, which are then incorporated into the water by groundwater or tidal flow.

Derivación biliopancreática de Larrad. Descripción de un modelo experimental en la rata / Larrad biliopancreatic diversion. Description of an rat experimental model

Objetivo. Validar un modelo experimental de derivación biliopancreática de Larrad (DBPL) y analizar las modificaciones ponderales y mortalidad en los animales operados alimentados con dieta estándar no suplementada. Material y metodo. Se utilizan 6 animales control y 10 operados, machos de la cepa Wistar. Se interviene al grupo de ratas operado con una adaptación de la técnica de Larrad en humanos: gastrectomía subcardial, canal biliopancreático corto creado a 5 cm del ángulo de Treitz y canal común a 5 cm de la válvula ileocecal. Tras un período de recuperación de 7 días las ratas se alimentan ad libitum con una dieta estándar no suplementada (sin proteínas, minerales o vitaminas), y se analiza el porcentaje de peso ganado o perdido. Resutados. Los animales control ganan peso progresivamente desde un 13,1 ± 2,4% en el día 7 hasta un 58 ± 9,2% en el día 63, momento en el que se los sacrificaba. Tras la DBPL la mortalidad es del 50% a los 25 ± 17,5 (rango, 14-56) días, sin diferencias significativas en el porcentaje de peso perdido entre los animales que sobrevivieron (­38,9 ± 14,2%) y los que fallecieron (­29 ± 5,6%; p = 0,192). El 80% de los animales que sobrevivieron perdieron peso progresivamente hasta alcanzar la máxima pérdida entre los 63 (­42,3 ± 8%) y 70 (­44,1 ± 9,7%) días. Un 20% de las ratas supervivientes perdieron peso hasta el día 35 y posteriormente recuperaron hasta un 7% el día del sacrificio (día 147). Conclusiones. El modelo experimental de DBPL es técnicamente factible. La mortalidad y el porcentaje de peso perdido no se encuentran directamente relacionados. El mecanismo de adaptación intestinal justificaría la recuperación de peso de los animales operados (AU)

Objective. To validate the experimental model of Larrad-biliopancreatic diversion (LBPD) and to analyze weight gain and mortality in rats fed with non­ supplemented diets. Material and method. Control (6) and experimental (10) male Wistar rats were used. The experimental group was operated on using the human LBPD adapted for rats: Subcardial gastrectomy, a short biliopancreatic channel created at 5 cm from Treitz angle and common channel at 5 cm from ileocecal valve. After surgery recovery (7 days) the rats were fed ab libitum with a standard non-supplemented diet (without proteins, minerals or vitamins). Percentage of weight lost or gained up to the end of the experiment was analyzed. Results. The control animals gained weight progressively from 13.1 ± 2.4% at day 7 to 58 ± 9.2% at day 63, when the animals were sacrificed. After LBPD, mortality was 50% at day 25 ± 17.5(range, 14-56), no significant differences in the percentage of weight lost being found between surviving (­38.9 ± 14.2%) and non-surviving rats (­29 ± 5.6%; p = 0.192). Of the surviving animals, 80% progressively lost weight reaching a maximum loss between day 63 (­42.3 ± 8%) and 70 (­44.1 ± 9.7%), and 20% lost weight until day 35 and gained over 7% of body weight until sacrifice (day 147). Conclusions. An experimental model of LBPD in rats is technically feasible. Both mortality and percentage weight loss are not directly related. The bowel adaptation mechanism could mediate the percentage of weight regain in operated rats (AU)