Bidirectional modulation of synaptic transmission by insulin-like growth factor-I.

Insulin-like growth factor-I (IGF-I) plays a key role in the modulation of synaptic plasticity and is an essential factor in learning and memory processes. However, during aging, IGF-I levels are decreased, and the effect of this decrease in the induction of synaptic plasticity remains unknown. Here we show that the induction of N-methyl-D-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP) at layer 2/3 pyramidal neurons (PNs) of the mouse barrel cortex is favored or prevented by IGF-I (10 nM) or IGF-I (7 nM), respectively, when IGF-I is applied 1 h before the induction of Hebbian LTP. Analyzing the cellular basis of this bidirectional control of synaptic plasticity, we observed that while 10 nM IGF-I generates LTP (LTPIGF-I) of the post-synaptic potentials (PSPs) by inducing long-term depression (LTD) of the inhibitory post-synaptic currents (IPSCs), 7 nM IGF-I generates LTD of the PSPs (LTDIGF-I) by inducing LTD of the excitatory post-synaptic currents (EPSCs). This bidirectional effect of IGF-I is supported by the observation of IGF-IR immunoreactivity at both excitatory and inhibitory synapses. Therefore, IGF-I controls the induction of Hebbian NMDAR-dependent plasticity depending on its concentration, revealing novel cellular mechanisms of IGF-I on synaptic plasticity and in the learning and memory machinery of the brain.

Retinopathy of Prematurity Outcomes of Neonates Meeting Only a Single Screening Criterion: Proposal of the TWO-ROP Algorithm.

PURPOSE: To assess the rates of retinopathy of prematurity (ROP) and treatment-warranted ROP in a modern set of patients meeting 0 or 1 of the current ROP screening criteria. DESIGN: Retrospective cohort study. METHODS: Single-center study of 9350 infants screened for ROP from 2009 to 2019. Rates of ROP and treatment-warranted ROP were evaluated in group 1 (birth weight [BW] <1500 g and gestational age [GA] ≥30 weeks), group 2 (BW ≥1500 g and GA <30 weeks), and group 3 (BW ≥1500 g and GA ≥30 weeks). RESULTS: Of 7520 patients with reported BW and GA, 1612 (21.4%) patients met the inclusion criteria. The number of patients in groups 1, 2, and 3 was 466 (6.19%), 23 (0.31%), and 1123 (14.93%), respectively. The number of patients diagnosed with ROP was 20 (4.29%) in group 1, 1 (4.35%) in group 2, and 12 (1.07%) in group 3 (P < .001). The mean interval between birth and ROP diagnosis was 36.25 days (range 12-75 days) in group 1, 47 days in group 2, and 23.33 days (range 10-39 days) in group 3 (P = .05). No cases of stage 3, zone 1, or plus disease were recorded. No patients met the treatment criteria. CONCLUSIONS: Patients meeting 1 screening criterion had a low rate of ROP (<5%), with no stage 3, zone 1, or plus disease. No patients required treatment. We propose a possible algorithm (TWO-ROP) in appropriate neonatal intensive care units, with an amendment in screening protocol for this low-risk population to include only an outpatient screening examination within 1 week of discharge, or at 40 weeks if inpatient, to decrease the inpatient ROP screening burden while maintaining safety. Further external validation of this protocol would be required.

The use of copper isotopes for understanding metal transfer mechanisms within the continuum mine-river-dam (Huelva Region, Spain).

Mining areas and in particular those containing massive sulfides have left a heavy environmental legacy with soils and hydrographic networks highly contaminated with metals and metalloids as for example in the Iberian Pyrite Belt (Huelva, Spain). Here, we present new data on copper (Cu) isotopic composition of waters and solids collected along a continuum Mine (Tharsis)-River (Meca)-Lake (Sancho) in the Iberian Pyrite Belt. Our results show that the isotopic signature of pit lakes is spatially variable, but remains stable over the seasons; this signature seems to be controlled by water-rock interaction processes. The data obtained on the Meca River imply a number of attenuation processes such as decrease in the metal concentration by precipitation of secondary minerals. This is accompanied by preferential retention of the heavy isotope (65Cu) with a possibility of living organisms (e.g., algae) participation. The terminal Sancho lake demonstrated constant isotopic signature over the entire depth of the water column despite sizable variations in Cu concentrations, which can be tentatively explained by a superposition of counter-interacting biotic and abiotic processes of Cu fractionation. Overall, the understanding of the isotopic variations along the hydrological continuum is useful for a better understanding of metal element transfer within mining environments and surrounding surface waters.

Low-dose proton radiotherapy for pediatric choroidal hemangioma: A case series.

Management of pediatric choroidal hemangioma complicated by large exudative retinal detachment can be challenging, with few options available. Limited data have been published on outcomes following proton radiotherapy (PRT) for management of these patients. In this retrospective case series, nine patients were treated with a low-dose PRT regimen of 20 Gy(relative biological effectiveness [RBE]) in 10 fractions, and two were treated with 15 Gy(RBE) in four fractions. Visual acuity improved in seven patients (64%) and remained stable in the remaining four (36%). In patients with imaging follow-up (10 patients), subretinal fluid resolved in nine patients (90%) and tumor thickness decreased or remained stable in 10 (100%). Complications were observed in eight of 11 patients (73%). One patient developed grade 2 cataract; otherwise, no grade ≥2 complications were observed.

Insulin regulates neurovascular coupling through astrocytes.

Mice with insulin receptor (IR)-deficient astrocytes (GFAP-IR knockout [KO] mice) show blunted responses to insulin and reduced brain glucose uptake, whereas IR-deficient astrocytes show disturbed mitochondrial responses to glucose. While exploring the functional impact of disturbed mitochondrial function in astrocytes, we observed that GFAP-IR KO mice show uncoupling of brain blood flow with glucose uptake. Since IR-deficient astrocytes show higher levels of reactive oxidant species (ROS), this leads to stimulation of hypoxia-inducible factor-1α and, consequently, of the vascular endothelial growth factor angiogenic pathway. Indeed, GFAP-IR KO mice show disturbed brain vascularity and blood flow that is normalized by treatment with the antioxidant N-acetylcysteine (NAC). NAC ameliorated high ROS levels, normalized angiogenic signaling and mitochondrial function in IR-deficient astrocytes, and normalized neurovascular coupling in GFAP-IR KO mice. Our results indicate that by modulating glucose uptake and angiogenesis, insulin receptors in astrocytes participate in neurovascular coupling.

Poly (L-Lactic Acid) Cell-Laden Scaffolds Applied on Swine Model of Tracheal Fistula.

INTRODUCTION: Tracheal fistula (TF) treatments may involve temporary orthosis and further ablative procedures, which can lead to infection. Thus, TF requires other therapy alternatives development. The hypothesis of this work was to demonstrate the feasibility of a tissue-engineered alternative for small TF in a preclinical model. Also, its association with suture filaments enriched with adipose tissue-derived mesenchymal stromal stem cells (AT-MSCs) was assessed to determine whether it could optimize the regenerative process. METHODS: Poly (L-Lactic acid) (PLLA) membranes were manufactured by electrospinning and had morphology analyzed by scanning electron microscopy. AT-MSCs were cultured in these scaffolds and in vitro assays were performed (cytotoxicity, cellular adhesion, and viability). Subsequently, these cellular constructs were implanted in an animal small TF model. The association with suture filaments containing attached AT-MSCs was present in one animal group. After 30 d, animals were sacrificed and regenerative potential was evaluated, mainly related to the extracellular matrix remodeling, by performing histopathological (Hematoxylin-Eosin and trichrome Masson) and immunohistochemistry (Collagen I/II/III, matrix metalloproteinases-2, matrix metalloproteinases-9, vascular endothelial growth factor, and interleukin-10) analyses. RESULTS: PLLA membranes presented porous fibers, randomly oriented. In vitro assays results showed that AT-MSCs attached were viable and maintained an active metabolism. Swine implanted with AT-MSCs attached to membranes and suture filaments showed aligned collagen fibers and a better regenerative progress in 30 d. CONCLUSIONS: PLLA membranes with AT-MSCs attached were useful to the extracellular matrix restoration and have a high potential for small TF treatment. Also, their association with suture filaments enriched with AT-MSCs was advantageous.

Outcomes of Primary Trabeculectomy versus Combined Phacoemulsification-Trabeculectomy Using Automated Electronic Health Record Data Extraction.

PURPOSE: Cataract is a known effect of trabeculectomy (TE), but some surgeons are hesitant to perform combined phacoemulsification-TE (PTE) due to a risk of increased TE failure. Herein, we compare intraocular pressure (IOP) lowering between trabeculectomy (TE) and phacoemulsification-TE (PTE) and investigate factors that impact patient outcomes. METHODS: We performed a retrospective study of adults undergoing primary TE or PTE at our institution from 2010 to 2017. We used Kaplan-Meier survival analysis to investigate time to TE failure, and Cox proportional hazards modeling to investigate predictors of TE failure, defined as undergoing a second glaucoma surgery or using more IOP-lowering medications than pre-operatively. RESULTS: 318 surgeries (218 TE; 100 PTE) from 268 patients were included. Median follow-up time was 753 days. Mean baseline IOP was 21.1 mmHg. There were no significant differences in IOP between TE and PTE groups beyond postoperative year 1, with 28.9-46.5% of TE and 35.5-44.4% of PTE groups achieving IOP ≤10. Final IOP was similar in both groups (p = 0.22): 12.41 (SD 4.18) mmHg in the TE group and 14.05 (SD 5.45) in the PTE group. 84 (26.4%) surgeries met failure criteria. After adjusting for surgery type, sex, age, race, surgeon, and glaucoma diagnosis there were no significant differences in TE failure. CONCLUSION: This study suggests there is no significant difference in the risk of TE failure in patients receiving TE versus those receiving PTE.

Biogeochemical indicators (waters/diatoms) of acid mine drainage pollution in the Odiel river (Iberian Pyritic Belt, SW Spain).

Odiel river basin is located in the Iberian Pyritic Belt (IPB) and mostly of its tributaries are severely affected by acid mine drainage (AMD). It is originated when pyritic minerals from abandoned mines, especially mineral residues from waste rock dams, get in contact with air and water. Fifteen sampling points were chosen to analyze interactions between diatom communities and water hydrogeochemistry. Considering physicochemical characteristics, sampling points were assigned as highly, moderately, and unpolluted by AMD. No correlation was observed between ecological diversity indexes and physico-chemical parameters. However, a dependency relationship between diatom species distribution and specific pH, conductivity, redox potential, sulfate, and metal concentrations was observed. Cluster analysis based on Pearson correlation and rs values of the non-parametric Spearman correlation allowed to identify Pinnularia acidophila, Pinnularia subcapitata var. elongata, and Eunotia exigua as the main bioindicators of AMD-polluted Odiel streams. Finally, a principal component analysis led to associate the most abundant diatoms species to specific physico-chemical parameters.

The Effect of Obstructive Sleep Apnea Treatment and Severity on Choroidal Thickness in Patients With Central Serous Chorioretinopathy.

Purpose: This work aimed to analyze the association of obstructive sleep apnea (OSA) with choroidal thickness (CT) in patients with central serous chorioretinopathy (CSC). Methods: We identified patients in the Stanford Research Repository with a diagnosis of CSC and OSA. Age- and sex-matched controls with either CSC or OSA only were also identified. CT was measured at 5 points (subfoveal, and 1500 and 3000 µm nasal and temporal) by 2 graders. In addition to OSA treatment and severity, we also investigated the association of Oxygen Desaturation Index and nocturnal oxygen saturation nadir with subfoveal CT (SFCT). Results: A total of 57 patients and 72 eyes met the study inclusion criteria. The mean SFCT was significantly different across the 3 groups: OSA-only was the thinnest, followed by CSC with OSA, and CSC-only was the thickest (194.2 µm, 295.1 µm, and 357.8 µm, respectively, P < .001). SFCT was thicker in CSC with OSA compared with those with only OSA (P < .05). OSA treatment status and OSA severity did not show a significant difference in SFCT in multivariable modeling. Nocturnal oxygen saturation nadir was positively associated with SFCT, but this did not reach significance.. Conclusions: SFCT is significantly different in patients with OSA alone, CSC with OSA, and CSC alone. While OSA treatment status did not demonstrate a significant difference in SFCT in this study, future studies should evaluate patients for OSA in patients known to have CSC and atypically thin CT to further investigate the novel metrics leveraged in this study.

Animal and Cellular Models of Alzheimer's Disease: Progress, Promise, and Future Approaches.

Alzheimer's disease (AD) is an incurable neurodegenerative disease affecting over 45 million people worldwide. Transgenic mouse models have made remarkable contributions toward clarifying the pathophysiological mechanisms behind the clinical manifestations of AD. However, the limited ability of these in vivo models to accurately replicate the biology of the human disease have precluded the translation of promising preclinical therapies to the clinic. In this review, we highlight several major pathogenic mechanisms of AD that were discovered using transgenic mouse models. Moreover, we discuss the shortcomings of current animal models and the need to develop reliable models for the sporadic form of the disease, which accounts for the majority of AD cases, as well as human cellular models to improve success in translating results into human treatments.

Cerebral dopamine neurotrophic factor transfection in dopamine neurons using neurotensin-polyplex nanoparticles reverses 6-hydroxydopamine-induced nigrostriatal neurodegeneration.

Overexpression of neurotrophic factors in nigral dopamine neurons is a promising approach to reverse neurodegeneration of the nigrostriatal dopamine system, a hallmark in Parkinson's disease. The human cerebral dopamine neurotrophic factor (hCDNF) has recently emerged as a strong candidate for Parkinson's disease therapy. This study shows that hCDNF expression in dopamine neurons using the neurotensin-polyplex nanoparticle system reverses 6-hydroxydopamine-induced morphological, biochemical, and behavioral alterations. Three independent electron microscopy techniques showed that the neurotensin-polyplex nanoparticles containing the hCDNF gene, ranging in size from 20 to 150 nm, enabled the expression of a secretable hCDNF in vitro. Their injection in the substantia nigra compacta on day 21 after the 6-hydroxydopamine lesion resulted in detectable hCDNF in dopamine neurons, whose levels remained constant throughout the study in the substantia nigra compacta and striatum. Compared with the lesioned group, tyrosine hydroxylase-positive (TH+) nigral cell population and TH+ fiber density rose in the substantia nigra compacta and striatum after hCDNF transfection. An increase in ßIII-tubulin and growth-associated protein 43 phospho-S41 (GAP43p) followed TH+ cell recovery, as well as dopamine and its catabolite levels. Partial reversal (80%) of drug-activated circling behavior and full recovery of spontaneous motor and non-motor behavior were achieved. Brain-derived neurotrophic factor recovery in dopamine neurons that also occurred suggests its participation in the neurotrophic effects. These findings support the potential of nanoparticle-mediated hCDNF gene delivery to develop a disease-modifying treatment against Parkinson's disease. The Institutional Animal Care and Use Committee of Centro de Investigación y de Estudios Avanzados approved our experimental procedures for animal use (authorization No. 162-15) on June 9, 2019.

Displasia mesenquimal placentaria asociada con restricción del crecimiento intrauterino de inicio temprano: reporte de un caso / Placental mesenchymal dysplasia associated with early onset intrauterine growth restriction: a case report

Resumen ANTECEDENTES: La displasia mesenquimal placentaria es una anomalía de la vasculatura y del tejido conectivo placentario que altera la estructura y la función de las vellosidades, se asocia con un desenlace perinatal adverso. CASO CLÍNICO: Paciente de 21 años, primigesta, con 15.2 semanas de embarazo establecidas por fetometría, con placenta corporal anterior, de morfología anormal, con múltiples imágenes hipoecogénicas que semejan racimos de uvas, sin flujo vascular en el Doppler color. La valoración ecográfica de las 33 semanas reportó fetometría para 27.2 semanas, anhidramnios y placentomagelia, con alteración en los parámetros de la flujometría Doppler. En la prueba sin estrés se diagnosticó restricción del crecimiento intrauterino estadio IV. La imagen del feto fue heterogénea en el flanco derecho de 4.7 x 4.1 cm. El embarazo finalizó por cesárea con una recién nacida con Apgar 8-9, de 930 gramos, placenta agrandada con vellosidades hidrópicas. El estudio histopatológico reportó: displasia mesenquimal placentaria. La resección del tumor abdominal fue electiva, por vía laparoscópica, al cuarto mes de vida, con diagnóstico histopatológico de hamartoma mesenquimal hepático. CONCLUSIÓN: La displasia mesenquimal placentaria es una anomalía placentaria benigna, relacionada con restricción del crecimiento intrauterino de inicio temprano que puede evolucionar, incluso, a la muerte del feto por hipoxia crónica debido a las anomalías en la vasculatura microscópica que afectan el desarrollo de las vellosidades terminales e interfiere en el intercambio de gases, nutrientes y electrolitos en el espacio intervelloso.

Abstract BACKGROUND: Placental mesenchymal dysplasia is an anomaly of the vasculature and placental connective tissue which alters the structure and function of the villi, being associated with an adverse perinatal outcome. CLINICAL CASE: Patient 21 years old, primigestation, with 15.2 weeks of pregnancy established by fetometry, with anterior body placenta, abnormal morphology, with multiple hypoechogenic images resembling clusters of grapes, without vascular flow in color Doppler. Ultrasound evaluation at 33 weeks, reporting fetometry for 27.2 weeks, anhydramnios and placentomagelia, with alteration in Doppler parameters, as well as in a non-stress test diagnosing fetal growth restriction stage IV. Fetus with heterogeneous image on the right flank of 4.7 x 4.1 cm. Abdominal pregnancy interruption was decided, obtaining a live female newborn, Apgar 8/9, weight 930 grams, enlarged placenta with hydropic villi. The histopathology study reports placental mesenchymal dysplasia. Abdominal tumor resection was performed electively by laparoscopy at 4 months of age with a histopathological diagnosis of hepatic mesenchymal hamartoma. CONCLUSION: Placental mesenchymal dysplasia is a benign placental anomaly, related to early-onset intrauterine growth restriction that can even progress to fetal death by chronic hypoxia due to abnormalities in the microscopic vasculature that affect the development of the terminal villi and interfere with the exchange of gases, nutrients and electrolytes in the intervillous space.

Macular Edema and Serous Macular Detachment after a Standard Dose of Intracameral Cefuroxime.

Intracameral cefuroxime has been associated with postoperative macular edema and sub-retinal fluid. To date, nearly all published cases are attributed to errors in antibiotic dilution, leading to administration of supratherapeutic doses. We report three cases of postoperative macular edema and subretinal fluid following a standard dose of 1 mg/0.1 mL of cefuroxime at the end of cataract surgery. Distinguishing features of these cases were intraoperative zonular instability and history of vitrectomy. We hypothesize that certain factors may increase the risk of cefuroxime-associated retinal toxicity, including history of vitrectomy, zonular compromise, posterior capsular break, surgery for a secondary intraocular lens, and unicameral state. [Ophthalmic Surg Lasers Imaging Retina. 2021;52:615-618.].

Plaque-Associated Oligomeric Amyloid-Beta Drives Early Synaptotoxicity in APP/PS1 Mice Hippocampus: Ultrastructural Pathology Analysis.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by initial memory impairments that progress to dementia. In this sense, synaptic dysfunction and loss have been established as the pathological features that best correlate with the typical early cognitive decline in this disease. At the histopathological level, post mortem AD brains typically exhibit intraneuronal neurofibrillary tangles (NFTs) along with the accumulation of amyloid-beta (Abeta) peptides in the form of extracellular deposits. Specifically, the oligomeric soluble forms of Abeta are considered the most synaptotoxic species. In addition, neuritic plaques are Abeta deposits surrounded by activated microglia and astroglia cells together with abnormal swellings of neuronal processes named dystrophic neurites. These periplaque aberrant neurites are mostly presynaptic elements and represent the first pathological indicator of synaptic dysfunction. In terms of losing synaptic proteins, the hippocampus is one of the brain regions most affected in AD patients. In this work, we report an early decline in spatial memory, along with hippocampal synaptic changes, in an amyloidogenic APP/PS1 transgenic model. Quantitative electron microscopy revealed a spatial synaptotoxic pattern around neuritic plaques with significant loss of periplaque synaptic terminals, showing rising synapse loss close to the border, especially in larger plaques. Moreover, dystrophic presynapses were filled with autophagic vesicles in detriment of the presynaptic vesicular density, probably interfering with synaptic function at very early synaptopathological disease stages. Electron immunogold labeling showed that the periphery of amyloid plaques, and the associated dystrophic neurites, was enriched in Abeta oligomers supporting an extracellular location of the synaptotoxins. Finally, the incubation of primary neurons with soluble fractions derived from 6-month-old APP/PS1 hippocampus induced significant loss of synaptic proteins, but not neuronal death. Indeed, this preclinical transgenic model could serve to investigate therapies targeted at initial stages of synaptic dysfunction relevant to the prodromal and early AD.

Contamination of multiuse eyedrop bottles by exhaled air from patients wearing face masks during the COVID-19 pandemic: Schlieren imaging analysis.

PURPOSE: To determine whether mask-induced redirected exhaled air through the superior mask gap contacts multiuse eyedrop bottles during drop administration and the efficacy of interventions to reduce such exposure. SETTING: Academic ophthalmology center. DESIGN: Interventional analysis. METHODS: Schlieren airflow imaging was taken of an examinee wearing frequently used face masks and enacting common clinical scenarios-with and without manual occlusion of the superior mask gap and/or neck extension-and maximum visible vertical breath plume height was quantified. Bottle height during eyedrop administration was measured for 4 ophthalmologists during instillation to 8 eyes of 4 subjects. RESULTS: Breath plume height (mean ± SD 275.5 ± 16.3 mm) was significantly greater than mean bottle height (13.9 ± 4.7 mm; P < .01). Plume height was reduced with manual mask occlusion vs without (P < .01) and was also lower than mean bottle height with manual mask occlusion (P < .01) but not in the absence of occlusion (P < .01). Neck extension alone did not adequately redirect liberated breath to prevent contact with a bottle. CONCLUSIONS: Exhaled air liberated from commonly worn patient face masks was able to contact multiuse eyedrop bottles during eyedrop administration. These findings have important patient safety implications during the coronavirus disease 2019 pandemic and with other respiratory pathogens because these multiuse bottles could potentially serve as vectors of disease. Occlusion of the superior mask gap significantly reduces breath contamination and should be strongly considered by eyecare providers during drop administration in eye clinics.

Novel transdermal bioadhesive surfactant-based system for release and solubility improvement of antimalarial drugs artemether-lumefantrine.

Artemether (ART) and lumefantrine (LUM) are the gold standard antimalarial drugs used for the treatment of malaria in children and pregnant women. Typically, ART and LUM are delivered orally in the form of a combined tablet, however, the appropriateness of this route of administration for these drugs is questionable due to the poor absorption and therefore bioavailability observed unless administered alongside lipid-rich foods. Transdermal drug delivery in the form of a patch-type system has been identified as a viable alternative to the conventional tablet-based therapy. A novel, surfactant-based ART-LUM formulation (S3AL), developed for transdermal delivery, may eliminate the shortcomings associated with oral delivery; namely poor drug absorption which is caused by the inherently low solubility of ART and LUM. Moreover, by successfully delivering these antimalarials transdermally, first-pass metabolism will be avoided leading to enhanced drug bioavailability in both cases. The S3AL formulation contained ART and LUM at equal concentrations (2.5% w/w of each) as well as Procetyl® AWS (30% w/w), oleic acid (10% w/w), 1-methyl-2-pyrrolidone (10% w/w), and water (45% w/w). The addition of LUM to the formulation changed the system from a striae structure to a dark field structure when visualized by a polarized light microscope. Additionally, this system possessed higher viscosity and superior skin bioadhesion, as evidenced by mechanical characterization, when compared to a similar formulation containing ART alone. S3AL was also proven to be biocompatible to human keratinocyte cells. Finally,in vitrostudies demonstrated the propensity of S3AL for successful delivery via the transdermal route, with 2279 ± 295 µg cm-2of ART and 94 ± 13 µg cm-2of LUM having permeated across dermatomed porcine skin after 24 h, highlighting its potential as a new candidate for the treatment of malaria.

Odiel River (SW Spain), a Singular Scenario Affected by Acid Mine Drainage (AMD): Graphical and Statistical Models to Assess Diatoms and Water Hydrogeochemistry Interactions.

The Odiel River (SW Spain) is one of the most cited rivers in the scientific literature due to its high pollution degree, generated by more than 80 sulphide mines' (mostly unrestored) contamination in the Iberian Pyritic Belt (IPB), that have been exploited for more than 5000 years. Along the river and its tributaries, the physico-chemical parameters and diatoms, from 15 sampling points, were analyzed in the laboratory. Physico-chemical parameters, water chemical analysis, together with richness and Shannon-Wiener indexes were integrated in a matrix. An initial graphical treatment allowed the definition and proposal of a functioning system model, as well as the establishment of cause-effect relationships between pollution and its effects on biota. Then, the proposed model was statistically validated by factor analysis. For acidic pH waters, high values of Eh, TDS, sulphate, ∑REE and ∑Ficklin were found, while diatomologic indicators took low values. Thus, factor analysis was a very effective tool for graphical treatment validation as well as for pollution-biota interaction models' formulation, governed by two factors: AMD processes and water balance suffered by the studied river. As a novelty, the cause-effect relationships between high barium concentration and low diversity and richness were demonstrated in the IPB, for the first time.

Non-productive angiogenesis disassembles Aß plaque-associated blood vessels.

The human Alzheimer's disease (AD) brain accumulates angiogenic markers but paradoxically, the cerebral microvasculature is reduced around Aß plaques. Here we demonstrate that angiogenesis is started near Aß plaques in both AD mouse models and human AD samples. However, endothelial cells express the molecular signature of non-productive angiogenesis (NPA) and accumulate, around Aß plaques, a tip cell marker and IB4 reactive vascular anomalies with reduced NOTCH activity. Notably, NPA induction by endothelial loss of presenilin, whose mutations cause familial AD and which activity has been shown to decrease with age, produced a similar vascular phenotype in the absence of Aß pathology. We also show that Aß plaque-associated NPA locally disassembles blood vessels, leaving behind vascular scars, and that microglial phagocytosis contributes to the local loss of endothelial cells. These results define the role of NPA and microglia in local blood vessel disassembly and highlight the vascular component of presenilin loss of function in AD.

Application of a Fuzzy Logic Based Methodology to Validate the Hydrochemical Characterization and Determining Seasonal Influence of a Watershed Affected by Acid Mine Drainage.

The Odiel River Basin, located in the Iberian Pyrite Belt (IPB), is heavily affected by acid mine drainage (AMD), which occurs when pyritic minerals from sulfide mining areas are exposed to atmospheric, hydrological or biological weathering. This paper presents a hydrochemical characterization of parameters in the Odiel River Basin by means of Fuzzy Logic and data mining methodologies to determine the seasonal influence of AMD in polluted waters that have not been used before for a basin in this environmental area. This technique was proven to be effective, providing results that could not be achieved by using classic statistics, because it allows us to characterize the different parameters separately and also their relationships in waters affected by AMD in a qualitative manner based on the antecedents and according to the conditions (rules) imposed by the consequents (in this case, the Fe(II) and accumulated rainfall over 30 days). Thus, it was possible to confirm that hydrochemistry is greatly affected by seasonal changes, with a higher pH in the wet season (up to 8.59) compared to 2.12, the minimum pH value reached in the dry season. Accordingly, higher concentrations of most of the metals were observed in the dry season (e.g., up to 4000 mg/L of Fe (II)), with the exception of the values found after the first rains that occur in the early fall. With the use of the Fuzzy Logic technique, it was observed that, during the wet season, lixiviates with a higher Fe content have higher metal concentrations, and in the dry season, the behavior is the opposite.