Experimental models of glaucoma: A powerful translational tool for the future development of new therapies for glaucoma in humans—A review of the literature

Glaucoma is a common complex disease that leads to irreversible blindness worldwide. Even though preclinical studies showed that lowering intraocular pressure (IOP) could prevent retinal ganglion cells loss, clinical evidence suggests that lessening IOP does not prevent glaucoma progression in all patients. Glaucoma is also becoming more prevalent in the elderly population, showing that age is a recognized major risk factor. Indeed, recent findings suggest that age-related tissue alterations contribute to the development of glaucoma and have encouraged exploration for new treatment approaches. In this review, we provide information on the most frequently used experimental models of glaucoma and describe their advantages and limitations. Additionally, we describe diverse animal models of glaucoma that can be potentially used in translational medicine and aid an efficient shift to the clinic. Experimental animal models have helped to understand the mechanisms of formation and evacuation of aqueous humor, and the maintenance of homeostasis of intra-ocular pressure. However, the transfer of pre-clinical results obtained from animal studies into clinical trials may be difficult since the type of study does not only depend on the type of therapy to be performed, but also on a series of factors observed both in the experimental period and the period of transfer to clinical application. Conclusions: Knowing the exact characteristics of each glaucoma experimental model could help to diminish inconveniences related to the process of the translation of results into clinical application in humans. © 2019 by the authors. Licensee MDPI, Basel, Switzerland

Análisis interregional utilizando una matriz insumo-producto bi-regional de Argentina

This paper presents a regional case study using a Bi-Regional Input-Output (BRIO) matrix of Buenos Aires City (BAC) and the Rest of Argentina (ROA), constructed from the Argentinian Input-Output matrix. A hybrid approach was applied to obtain the BRIO matrix, which combines pure non-survey methods with matrix-balancing methods like RAS or Cross-Entropy. Once the BRIO matrix was obtained, our study has focused on analyzing the BAC regional structure and the interconnections between regions. We have also estimated the regional and national carbon footprint for the BAC and Argentina, respectively. Results show that service and industry sectors play an important role in the economy of BAC and some of them have strong interregional spillover effects over the rest of the country. In addition, the results also show that sectors on BAC with the highest regional multipliers are also the ones with highest emissions.Este artículo presenta un caso de estudio regional utilizando una matriz Bi-Regional Input-Output (BRIO) de la Ciudad de Buenos Aires (BAC) y el Resto de Argentina (ROA), construida a partir de la matriz Input-Output de Argentina. Se ha utilizado una metodología híbrida para obtener la matriz BRIO, la cual combina métodos indirectos puros y métodos de calibración de matrices como RAS y Entropía Cruzada. Una vez obtenida la matriz BRIO, nuestro estudio se ha centrado en analizar la estructura regional de la BAC y las interconexiones entre regiones. También hemos realizado la estimación de la huella de carbono nacional y regional para Argentina y en la BAC, respectivamente. Los resultados muestran que los sectores de servicios e industria juegan un papel importante en la economía de la BAC y algunos de ellos tienen fuertes efectos indirectos interregionales sobre el resto del país. Además, los resultados también muestran que los sectores de la BAC con los multiplicadores regionales más altos también son los que tienen las emisiones más altas

Enhanced at puberty 1 (EAP1) is a new transcriptional regulator of the female neuroendocrine reproductive axis

The initiation of mammalian puberty and the maintenance of female reproductive cycles are events controlled by hypothalamic neurons that secrete the decapeptide gonadotropin-releasing hormone (GnRH). GnRH secretion is, in turn, controlled by changes in neuronal and glial inputs to GnRH-producing neurons. The hierarchical control of the process is unknown, but it requires coordinated regulation of these cell-cell interactions. Here we report the functional characterization of a gene (termed enhanced at puberty 1 [EAP1]) that appears to act as an upstream transcriptional regulator of neuronal networks controlling female reproductive function. EAP1 expression increased selectively at puberty in both the nonhuman primate and rodent hypothalamus. EAP1 encoded a nuclear protein expressed in neurons involved in the inhibitory and facilitatory control of reproduction. EAP1 transactivated genes required for reproductive function, such as GNRH1, and repressed inhibitory genes, such as preproenkephalin. It contained a RING finger domain of the C3HC4 subclass required for this dual transcriptional activity. Inhibition of EAP1 expression, targeted to the rodent hypothalamus via lentivirus-mediated delivery of EAP1 siRNAs, delayed puberty, disrupted estrous cyclicity, and resulted in ovarian abnormalities. These results suggest that EAP1 is a transcriptional regulator that, acting within the neuroendocrine brain, contributes to controlling female reproductive function.This work was supported by grants from the NIH, the National Institute of Child Health and Human Development/NIH (to S.R. Ojeda), the European Society for Paediatric Endocrinology (to H. Jung), the German Research Foundation (to S. Heger), and the European Commission (PIONEER to S. Heger)

Chronic fluoxetine treatment increases daytime melatonin synthesis in the rodent

Circadian rhythm disturbances can occur as part of the clinical symptoms of major depressive disorder and have been found to resolve with antidepressant therapy. The pineal gland is relevant to circadian rhythms as it secretes the hormone melatonin following activation of the cyclic adenosine monophosphate (cAMP) signaling cascade and of arylalkylamine N-acetyltransferase (AA-NAT), the rate-limiting enzyme for its synthesis. Cyclic AMP is synthesized by adenylate cyclases (AC) and degraded by phosphodiesterases (PDEs). Little is known about the contribution of the PDE system to antidepressant-induced alterations in pineal cAMP signaling and melatonin synthesis. In the present study we used enzyme immunoassay to measure plasma melatonin levels and pineal cAMP levels and as well as quantitative real-time polymerase chain reaction to measure pineal expression of PDE, AC, and AA-NAT genes in rats chronically treated with the prototypic antidepressant fluoxetine. We found elevated melatonin synthesis with increased pineal AA-NAT gene expression and daytime plasma melatonin levels and downregulated cAMP signaling with increased PDE and unchanged AC pineal gene expression, and decreased content of pineal cAMP. We conclude that chronic fluoxetine treatment increases daytime plasma melatonin and pineal AA-NAT gene expression despite downregulated pineal cAMP signaling in the rodent

The use of dried blood spot sampling for the measurement of HbA1c: a cross-sectional study

BACKGROUND: The use of dried blood spot (DBS) sampling is an alternative to traditional venous blood collection, and particularly useful for people living in rural and remote areas, and for those who are infirm, house-bound or time-poor. The objective of this study was to assess whether the measurement of glycated haemoglobin A1c (HbA1c) in DBS samples provided comparative and acceptably precise results. METHODS: Venous and capillary blood samples were collected from 115 adult participants. After proper instruction, each participant punctured his/her own finger and collected capillary blood samples on pieces of a proprietary cellulose filter paper. Each filter paper was subsequently placed inside a breathable envelope, stored at room temperature, and processed on the same day (D0), four (D4), seven (D7) and fourteen (D14) days after collection. HbA1c was measured in duplicates/triplicates in whole venous blood (WB), capillary blood (capDBS) and venous blood placed on the matrix paper (venDBS), by turbidimetric inhibition immunoassay. Intra-assay coefficients of variation (CV) were calculated. DBS values were compared to WB results using linear regression, Bland-Altman plots and cross-validation models. RESULTS: Eleven and 56 patients had type 1 and type 2 diabetes mellitus, respectively. Mean HbA1c levels were 6.22 ± 1.11 % for WB samples (n = 115). The median intra-assay CV was lower than 3 % for WB and capDBS on all days. Results from capDBS and venDBS showed high correlation and agreement to WB results, with narrow 95 % limits of agreement (except for results from D14 samples), as observed in Bland-Altman plots. When capDBS values were applied to equations derived from regression analyses, results approached those of WB values. A cross-validation model showed that capDBS results on D0, D4 and D7 were close to the WB results, with prediction intervals that were narrow enough to be clinically acceptable. CONCLUSIONS: The measurement of HbA1c from DBS samples provided results that were comparable to results from WB samples, if measured up to seven days after collection. Intra-assay coefficients of variation were low, results were in agreement with the gold-standard, and prediction intervals were clinically acceptable. The measurement of HbA1c through DBS sampling may be considered in situations where traditional venipuncture is not available.This study was funded by MyHealthTest Pty, including the article-processing charge

E007 Differential effects of microparticles from human apoptotic T lymphocytes and from human apoptotic monocytes in endothelial cells

During cell activation or apoptosis, cells release vesicles, also called microparticles (MPs) from the plasma membrane. Since composition of MPs is dependent on cell origin and the type of stimulation, we compared the effects of MPs generated from both apoptotic T lymphocytes and apoptotic monocytes on endothelial function with respect to both nitric oxide (NO) pathway and reactive oxygen species (ROS). MPs were produced by treatment of either human T lymphocytes with the apoptotic agent actinomycin D or human monocytic cell line THP-1 with the apoptotic agent, the etoposide VP-16. Human Eahy 926 endothelial cells were incubated with 10μg/ml MPs for 24h. Apoptotic MPs from human T lymphocytes decreased NO production that was associated with overexpression and phosphorylation of endothelial NOsynthase (eNOS). Also, T lymphocytes MPs enhanced expression of caveolin-1 and decreased its phosphorylation. T lymphocytes MPs enhanced ROS by a mechanism sensitive to xanthine oxidase and P-IkappaBalpha inhibitors. PI3-kinase inhibition reduced the effects of T lymphocytes MPs on eNOS, but not on caveolin-1, whereas it enhanced the effects of MPs on ROS production. Inhibition of MEK reversed eNOS phosphorylation but it had no effect on ROS production induced by T lymphocytes MPs. By contrast, apoptotic MPs from human monocytes increased both NO production and in much less extent ROS. These effects were associated with a decrease of caveolin-1 expression and increased its phosphorylation, without affecting eNOS expression and phosphorylation. The inhibitor of the PI-3kinase, LY294002, reversed the effects of monocyte MPs on caveolin-1 expression but not on its phosphorylation. The MEK1/2 inhibitor, U0126, reversed the decrease of caveolin-1 expression induced by MPs from monocytes. Interestingly, U0126 potentiated ROS production induced by monocyte MPs. Whereas in vivo injection of T lymphocytes MPs in mice impaired endothelial function, apoptotic MPs from human monocytes did not affect endothelium-dependent relaxation. In addition, monocyte MPs were able to promote in vitro angiogenesis. In summary, these results highlight differential effects of apoptotic MPs from different origins by activating diverse multiple pathways related to NO and ROS productions

Inclusion of motor evoked abnormalities in amyotrophic lateral sclerosis: a diagnostic algorithm to early classify lower motor neuron phenotypes

no abstrac

The Mechanism of Action of Cytokines to Control the Release of Hypothalamic and Pituitary Hormones in Infection

Abstract: During infection, bacterial and viral products, such as bacterial lipopolysaccharide (LPS), cause the release of cytokines from immune cells. These cytokines can reach the brain by several routes. Furthermore, cytokines, such as interleukin‐1 (IL‐1), are induced in neurons within the brain by systemic injection of LPS. These cytokines determine the pattern of hypothalamic‐pituitary secretion that characterizes infection. IL‐2, by stimulation of cholinergic neurons, activates neural nitric oxide synthase (nNOS). The nitric oxide (NO) released diffuses into corticotropin‐releasing hormone (CRH)‐secreting neurons and releases CRH. IL‐2 also acts in the pituitary to stimulate adrenocorticotropic hormone (ACTH) secretion. On the other hand, IL‐1α blocks the NO‐induced release of luteinizing hormone‐releasing hormone (LHRH) from LHRH neurons, thereby blocking pulsatile LH but not follicle‐stimulating hormone (FSH) release and also inhibiting sex behavior that is induced by LHRH. IL‐1α and granulocyte macrophage colony‐stimulating factor (GMCSF) block the response of the LHRH terminals to NO. The mechanism of action of GMCSF to inhibit LHRH release is as follows. It acts on its receptors on γ‐aminobutyric acid (GABA)ergic neurons to stimulate GABA release. GABA acts on GABAa receptors on the LHRH neuronal terminal to block NOergic stimulation of LHRH release. IL‐1α inhibits growth hormone (GH) release by inhibiting GH‐releasing hormone (GHRH) release, which is mediated by NO, and stimulating somatostatin release, also mediated by NO. IL‐1α‐induced stimulation of PRL release is also mediated by intra‐hypothlamic action of NO, which inhibits release of the PRL‐inhibiting hormone dopamine. The actions of NO are brought about by its combined activation of guanylate cyclase‐liberating cyclic guanosine monophosphate (cGMP) and activation of cyclooxygenase (COX) and lipoxygenase (LOX) with liberation of prostaglandin E2 and leukotrienes, respectively. Thus, NO plays a key role in inducing the changes in release of hypothalamic peptides induced in infection by cytokines. Cytokines, such as IL‐1β, also act in the anterior pituitary gland, at least in part via induction of inducible NOS. The NO produced inhibits release of ACTH. The adipocyte hormone leptin, a member of the cytokine family, has largely opposite actions to those of the proinflammatory cytokines, stimulating the release of FSHRF and LHRH from the hypothalamus and FSH and LH from the pituitary directly by NO.Fil: McCann, Samuel M.. Pennington Biomedical Research Center; Estados UnidosFil: Kimura, M.. Medical and Dental University; JapónFil: Karanth, S.. Pennington Biomedical Research Center; Estados UnidosFil: Yu, W. H.. Pennington Biomedical Research Center; Estados UnidosFil: Mastronardi, C. A.. Pennington Biomedical Research Center; Estados UnidosFil: Besuhli, Valeria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentin

Design, fabrication and characterization of piezoelectric cantilever MEMS for underwater application

This work shows a preliminary microfabrication route for a novel directional hydrophone based on a cross-shaped design of piezoelectric cantilevers. A thin layer of aluminum nitride (AlN) using Molybdenum (Mo) thin film as electrodes will be exploited as piezoelectric functional layer for the microfabrication of a cantilever-based ultrasonic micro electro mechanical system (MEMS) hydrophone. A parameterized simulation based on length of these cantilevers between 100 and 1000 μm allowed to set the first resonant mode between 20 kHz and 200 kHz, the desired underwater ultrasonic acoustic range. The microsystem was designed with cantilevers facing each other in a cross configuration in order to have novel MEMS hydrophone with an omnidirectional response. In order to investigate the first resonance frequency mode and displacement measurements, a Laser Doppler Vibrometer was used and good agreement between simulations and experimental results was achieved. Responsivity and directionality measurements of the piezoelectric MEMS cantilevers were performed in water. Maximum sensitivity up to −153 dB with omnidirectional directivity pattern was achieved by fabricated MEMS sensor

Myalgic encephalomyelitis/chronic fatigue syndrome: A comprehensive review

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating chronic disease of unknown aetiology that is recognized by the World Health Organization (WHO) and the United States Center for Disease Control and Prevention (US CDC) as a disorder of the brain. The disease predominantly affects adults, with a peak age of onset of between 20 and 45 years with a female to male ratio of 3:1. Although the clinical features of the disease have been well established within diagnostic criteria, the diagnosis of ME/CFS is still of exclusion, meaning that other medical conditions must be ruled out. The pathophysiological mechanisms are unclear but the neuro-immuno-endocrinological pattern of CFS patients gleaned from various studies indicates that these three pillars may be the key point to understand the complexity of the disease. At the moment, there are no specific pharmacological therapies to treat the disease, but several studies’ aims and therapeutic approaches have been described in order to benefit patients’ prognosis, symptomatology relief, and the recovery of pre-existing function. This review presents a pathophysiological approach to understanding the essential concepts of ME/CFS, with an emphasis on the population, clinical, and genetic concepts associated with ME/CFS. © 2019 by the authors